Azaquinazoline Inhibitors of Atypical Protein Kinase C

ABSTRACT

The present application provides a compound of formula (1) 
     
       
         
         
             
             
         
       
     
     or a salt thereof, wherein R 7 , R 8 , R 9 , G, and X are as defined herein. This application further describes compositions comprising the same. Compounds of formula (I) and their salts have aPKC inhibitory activity, and may be used to treat proliferative diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Nos.61/707,340, filed Sep. 28, 2012 and 61/781,364, filed Mar. 14, 2013, thedisclosures of which are incorporated herein by reference in theirentireties.

BACKGROUND

PKCι and PKCζ (accession numbers NM_002740 and NM_002744 respectively)together define the atypical sub-class of the protein kinase C (PKC)family. The aPKCs are structurally and functionally distinct from theother PKC sub-classes, classic/conventional and novel, as theircatalytic activity is not dependent on diacylglycerol and calcium (Ono,Y., Fujii, T., Ogita, K., Kikkawa, U., Igarashi, K., and Nishizuka, Y.(1989). Protein kinase C zeta subspecies from rat brain: its structure,expression, and properties. Proc Natl Acad Sci USA 86, 3099-3103).

Structurally, PKCι and PKCζ contain a C-terminal serine/threonine kinasedomain (AGC class) and an N-terminal regulatory region containing a PhoxBem 1 (PB 1) domain involved in mediating protein:protein interactionscritical for aPKC function. At the amino acid level the aPKCs share 72%overall homology, however, the kinase domains share 84% identity anddiffer in the active site by just a single amino acid. This strikinghomology suggests an ATP-competitive ligand would not be expected toexhibit significant aPKC isoform selectivity.

The aPKCs have been implicated in a diverse number of signallingpathways, demonstrating both redundant and distinct signallingfunctions. Both isoforms have emerged as central players in themechanisms that regulate the establishment and maintenance of cellularpolarity in multiple cell types (reviewed in Suzuki, A., and Ohno, S.(2006). The PAR-aPKC system: lessons in polarity. J Cell Sci 119,979-987). Genetic dissection of their functions using knockout mice havealso revealed preferential roles for PKCζ in the regulation of NF-kBsignalling (Leitges, M., Sanz, L., Martin, P., Duran, A., Braun, U.,Garcia, J. F., Camacho, F., Diaz-Meco, M. T., Rennert, P. D., andMoscat, J. (2001). Targeted disruption of the zetaPKC gene results inthe impairment of the NF-kappaB pathway. Mol Cell 8, 771-780), and PKCιin insulin secretion and action (Farese, R. V., Sajan, M. P., Yang, H.,Li, P., Mastorides, S., Gower, W. R., Jr., Nimal, S., Choi, C. S., Kim,S., Shulman, G. I., et al. (2007). Muscle-specific knockout ofPKC-lambda impairs glucose transport and induces metabolic and diabeticsyndromes. J Clin Invest 117, 2289-2301). In addition, both isoformshave been implicated in the pathogenesis of cancer making a strong casefor the inhibition of the aPKCs as a novel therapeutic avenue.

PKCι is a known oncogene in non-small cell lung cancer (NSCLC). In onestudy it was shown to be overexpressed in 69% of NSCLC cases at theprotein level. Consistent with this, the PKCι gene (PRKCI residing onchromosome 3q26) was shown to be amplified in 36.5% of NSCLC tumoursexamined, including 96% of the squamous cell carcinoma sub-type (Regala,R. P., Weems, C., Jamieson, L., Khoor, A., Edell, E. S., Lohse, C. M.,and Fields, A. P. (2005b). Atypical protein kinase C iota is an oncogenein human non-small cell lung cancer. Cancer Res 65, 8905-8911).Amplification of 3q26 has also been reported in 44% of ovarian cancers,including >70% of serous epithelial ovarian cancers where 3q26amplification is translated into increased PKCι protein expression.Moreover, increased PKCι expression is associated with poor prognosis inNSCLC and ovarian cancer where it may serve as a diagnostic biomarker ofaggressive disease (Eder, A. M., Sui, X., Rosen, D. G., Nolden, L. K.,Cheng, K. W., Lahad, J. P., Kango-Singh, M., Lu, K. H., Warneke, C. L.,Atkinson, E. N., et al. (2005). Atypical PKCiota contributes to poorprognosis through loss of apical-basal polarity and cyclin Eoverexpression in ovarian cancer. Proc Natl Acad Sci USA 102,12519-12524; Zhang, L., Huang, J., Yang, N., Liang, S., Barchetti, A.,Giannakakis, A., Cadungog, M. G., O'Brien-Jenkins, A., Massobrio, M.,Roby, K. F., et al. (2006). Integrative genomic analysis of proteinkinase C (PKC) family identifies PKCiota as a biomarker and potentialoncogene in ovarian carcinoma. Cancer Res 66, 4627-4635). 3q26amplifications have been observed in many other cancers includingoesophageal squamous cell carcinoma (Yang, Y. L., Chu, J. Y., Luo, M.L., Wu, Y. P., Zhang, Y., Feng, Y. B., Shi, Z. Z., Xu, X., Han, Y. L.,Cai, Y., et al. (2008). Amplification of PRKCI, located in 3q26, isassociated with lymph node metastasis in esophageal squamous cellcarcinoma. Genes Chromosomes Cancer 47, 127-136) and breast cancer(Kojima, Y., Akimoto, K., Nagashima, Y., Ishiguro, H., Shirai, S.,Chishima, T., Ichikawa, Y., Ishikawa, T., Sasaki, T., Kubota, Y., et al.(2008). The overexpression and altered localization of the atypicalprotein kinase C lambda/iota in breast cancer correlates with thepathologic type of these tumors. Hum Pathol 39, 824-831) suggesting thatPKCι may also participate in the pathogenesis of these diseases.

In NSCLC the primary function of PKCι is to drive transformed growth viaa Rac1/PAK/MEK/ERK signalling axis. However, PKCι also functions inNSCLC survival, resistance to chemotherapy, and invasion via distinctpathways (reviewed in Fields, A. P., and Regala, R. P. (2007). Proteinkinase C iota: human oncogene, prognostic marker and therapeutic target.Pharmacol Res 55, 487-497). In ovarian cancer transformed growth iscorrelated with deregulated epithelial cell polarity and increased cycleE expression (Eder et al., 2005) suggesting that PKCι can influence thecancer phenotype through multiple mechanisms. Compelling evidence hasemerged to suggest that inhibition of PKCι may be a useful therapeuticapproach to combat tumours characterised by increased PKCι expression.In transgenic models, mice with elevated PKCι activity in the colon aremore susceptible to carcinogen-induced colon carcinogenesis, andexpression of a kinase-dead mutant of PKCι blocks the transformation ofintestinal cells by oncogenic Ras (Murray, N. R., Jamieson, L., Yu, W.,Zhang, J., Gokmen-Polar, Y., Sier, D., Anastasiadis, P., Gatalica, Z.,Thompson, E. A., and Fields, A. P. (2004). Protein kinase Ciota isrequired for Ras transformation and colon carcinogenesis in vivo. J CellBiol 164, 797-802). Finally, genetic or pharmacological inhibition ofPKCι by a gold derivative—aurothiomalate (ATM)—blocks the growth ofNSCLC cells in soft agar and significantly decreases tumour volume inxenograft models of NSCLC(Regala, R. P., Thompson, E. A., and Fields, A.P. (2008). Atypical protein kinase C iota expression and aurothiomalatesensitivity in human lung cancer cells. Cancer Res 68, 5888-5895;Regala, R. P., Weems, C., Jamieson, L., Copland, J. A., Thompson, E. A.,and Fields, A. P. (2005a). Atypical protein kinase Ciota plays acritical role in human lung cancer cell growth and tumorigenicity. JBiol Chem 280, 31109-31115).

Despite the high degree of similarity between aPKC isoforms, the role ofPKCζ in cancer is distinct from that of PKCι. PKCζ plays a role in NSCLCcell survival by phosphorylating and antagonising the pro-apoptoticeffects of Bax in response to nicotine (Xin, M., Gao, F., May, W. S.,Flagg, T., and Deng, X. (2007). Protein kinase Czeta abrogates theproapoptotic function of Bax through phosphorylation. J Biol Chem 282,21268-21277). PKCζ activity has also been linked to resistance against awide range of cytotoxic and genotoxic agents. For instance, in humanleukaemia cells, overexpression of PKCζ confers resistance against1-β-D-arabinofuranosylcytosine (ara-C), daunorubicin, etoposide, andmitoxantrone-induced apoptosis (Filomenko, R., Poirson-Bichat, F.,Billerey, C., Belon, J. P., Garrido, C., Solary, E., and Bettaieb, A.(2002). Atypical protein kinase C zeta as a target forchemosensitization of tumor cells. Cancer Res 62, 1815-1821; Plo, I.,Hernandez, H., Kohlhagen, G., Lautier, D., Pommier, Y., and Laurent, G.(2002). Overexpression of the atypical protein kinase C zeta reducestopoisomerase II catalytic activity, cleavable complexes formation, anddrug-induced cytotoxicity in monocytic U937 leukemia cells. J Biol Chem277, 31407-31415). Furthermore, inhibition of PKCζ activity throughexpression of a kinase-dead mutant sensitises leukaemia cells to thecytotoxic effects of etoposide both in vitro and in vivo (Filomenko etal., 2002). Atypical protein kinase C regulates dual pathways fordegradation of the oncogenic coactivator SRC-3/AIB1. Mol Cell 29,465-476), and both of these proteins have been postulated to play a rolein tamoxifen resistance in breast cancer (Iorns, E., Lord, C. J., andAshworth, A. (2009). Parallel RNAi and compound screens identify thePDK1 pathway as a target for tamoxifen sensitization. Biochem J 417,361-370; Osborne, C. K., Bardou, V., Hopp, T. A., Chamness, G. C.,Hilsenbeck, S. G., Fuqua, S. A., Wong, J., Allred, D. C., Clark, G. M.,and Schiff, R. (2003). Role of the estrogen receptor coactivator AIB1(SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J NatlCancer Inst 95, 353-361). Together these studies suggest that inhibitionof PKCζ activity may have beneficial therapeutic effects by acting as achemosensitiser to a wide array of commonly used chemotoxic agents inthe clinic.

Further evidence that small molecule inhibition of PKCζ could haveimportant therapeutic benefits has recently emerged from tumour modelsthat link PKCζ signalling to the mTOR pathway. PKCζ is constitutivelyactivated in follicular lymphoma and has been identified as a noveltarget for the anti-CD20 therapeutic antibody rituximab (Leseux, L.,Laurent, G., Laurent, C., Rigo, M., Blanc, A., Olive, D., and Bezombes,C. (2008). PKC zeta mTOR pathway: a new target for rituximab therapy infollicular lymphoma. Blood 111, 285-291). Rituximab inhibits follicularlymphoma proliferation by targeting a PKCζ-MAPK-mTOR pathway, suggestingthat PKCζ is both a target of Rituximab, and a key regulator of its'anti-leukaemic effect. Regulation of the mTOR/p70S6K pathway by PKCζ hasalso been implicated in the transition of prostate cancer cells to anandrogen-independent state (Inoue, T., Yoshida, T., Shimizu, Y.,Kobayashi, T., Yamasaki, T., Toda, Y., Segawa, T., Kamoto, T., Nakamura,E., and Ogawa, O. (2006). Requirement of androgen-dependent activationof protein kinase Czeta for androgen-dependent cell proliferation inLNCaP Cells and its roles in transition to androgen-independent cells.Mol Endocrinol 20, 3053-3069). Finally, mice containing a homozygousdeletion of Par4, a negative regulator of PKCζ, exhibit greatly enhancedPKCζ activity. These mice spontaneously develop tumours of the prostateand endometrium, and potentiate Ras-induced lung carcinogenesisconsistent with a role for PKCζ in lung cancer (Garcia-Cao, I., Duran,A., Collado, M., Carrascosa, M. J., Martin-Caballero, J., Flores, J. M.,Diaz-Meco, M. T., Moscat, J., and Serrano, M. (2005). Tumour-suppressionactivity of the proapoptotic regulator Par4. EMBO Rep 6, 577-583; Joshi,J., Fernandez-Marcos, P. J., Galvez, A., Amanchy, R., Linares, J. F.,Duran, A., Pathrose, P., Leitges, M., Canamero, M., Collado, M., et al.(2008). Par-4 inhibits Akt and suppresses Ras-induced lungtumorigenesis. EMBO J 27, 2181-2193).

SUMMARY

The application provides a compound of formula (I)

or a salt thereof, wherein R⁷, R⁸, R⁹, G, and X are as defined herein.

A compound of formula (I) and its salts have aPKC inhibitory activity,and may be used to treat aPKC-dependent disorders or conditions.

The present application further provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with at least one pharmaceutically acceptablecarrier, diluent, or excipient therefor.

In another aspect, the present application provides a method of treatinga subject suffering from an aPKC-dependent disorder or conditioncomprising: administering to the subject a compound of formula (I) or apharmaceutically acceptable salt thereof.

The present application further provides a method of treating aproliferative disorder in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION I. Definitions

-   “About” as used herein when referring to a measurable value such as    an amount, a temporal duration, and the like, is meant to encompass    reasonable variations of the value, such as, for example, ±10% from    the specified value. For example, the phrase “about 50” encompasses    reasonable variations of 50, such as ±10% of the numerical value 50,    or from 45 to 55.-   “Alkyl” or “alkyl group” refers to a monoradical of a branched or    unbranched saturated hydrocarbon chain. Examples include, but are    not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,    n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl,    isobutyl, etc. Alkyl groups typically contain 1-10 carbon atoms,    such as 1-6 carbon atoms or 1-4 carbon atoms, and can be substituted    or unsubstituted.-   “Alkylene” or “alkylene group” refers to a diradical of a branched    or unbranched saturated hydrocarbon chain. Examples include, but are    not limited to, methylene (—CH₂—), the ethylene isomers (—CH(CH₃)—    and —CH₂CH₂—), the propylene isomers (—CH(CH₃)CH₂—, —CH(CH₂CH₃)—,    —C(CH₃)₂—, and —CH₂CH₂CH₂—), etc. Alkylene groups typically contain    1-10 carbon atoms, such as 1-6 carbon atoms, and can be substituted    or unsubstituted.-   “Alkenyl” or “alkenyl group” refers to a monoradical of a branched    or unbranched hydrocarbon chain containing at least one double bond.    Examples include, but are not limited to, ethenyl, 3-buten-1-yl,    2-ethenylbutyl, and 3-hexen-1-yl. Alkenyl groups typically contain    2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and    can be substituted or unsubstituted.-   “Alkynyl” or “alkynyl group” refers to a monoradical of a branched    or unbranched hydrocarbon chain containing at least one triple bond.    Examples include, but are not limited to, ethynyl, 3-butyn-1-yl,    propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl. Alkynyl groups typically    contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon    atoms, and can be substituted or unsubstituted.-   “Aryl” or “aryl group” refers to phenyl and 7-15 membered    monoradical bicyclic or tricyclic hydrocarbon ring systems,    including bridged, spiro, and/or fused ring systems, in which at    least one of the rings is aromatic. Aryl groups can be substituted    or unsubstituted. Examples include, but are not limited to,    naphthyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl,    6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and    6,7,8,9-tetrahydro-5H-benzocycloheptenyl. An aryl group may contain    6 (i.e., phenyl) or 9 to 15 ring atoms, such as 6 (i.e., phenyl) or    9-11 ring atoms, e.g., 6 (i.e., phenyl), 9 or 10 ring atoms.-   “Arylene” or “arylene group” refers to a phenylene (—C₆H₄—) or a    7-15 membered diradical bicyclic or tricyclic hydrocarbon ring    systems, including bridged, spiro, and/or fused ring systems, in    which at least one of the rings is aromatic. Arylene groups can be    substituted or unsubstituted. For example, an arylene group may    contain 6 (i.e., phenylene) or 9 to 15 ring atoms; such as 6 (i.e.,    phenylene) or 9-11 ring atoms; e.g., 6 (i.e., phenylene), 9 or 10    ring atoms. An arylene group can also include ring systems    substituted on ring carbons with one or more —OH functional groups    (which may further tautomerize to give a ring C═O group).-   “Arylalkyl” or “arylalkyl group” refers to an alkyl group in which a    hydrogen atom is replaced by an aryl group, wherein alkyl group and    aryl group are as previously defined (i.e., arylalkyl-). Arylalkyl    groups can be substituted or unsubstituted. Examples include, but    are not limited to, benzyl (C₆H5CH₂—).-   “Cycloalkyl” or “cycloalkyl group” refers to a monoradical    non-aromatic carbocyclic ring system, which may be saturated or    unsaturated, substituted or unsubstituted, and may be monocyclic,    bicyclic, or tricyclic, and may be bridged, spiro, and/or fused.    Examples include, but are not limited to, cyclopropyl,    cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,    cyclohexyl, cyclohexenyl, norbornyl, norbornenyl,    bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene,    bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane,    bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and    bicyclo[3.3.2]decane. The cycloalkyl group may contain from 3 to 10    ring atoms, such as 3 to 7 ring atoms (e.g., 3 ring atoms, 5 ring    atoms, 6 ring atoms, or 7 ring atoms).-   “Cycloalkylalkyl” or “cycloalkylalkyl group” refers to an alkyl    group in which a hydrogen atom is replaced by a cycloalkyl group,    wherein alkyl group and cycloalkyl group are as previously defined    (i.e., cycloalkylalkyl-). Cycloalkylalkyl groups can be substituted    or unsubstituted. Examples include, but are not limited to,    cyclohexylmethyl (C₆H₁₁CH₂—).-   “Haloalkyl” or “haloalkyl group” refers to alkyl groups in which one    or more hydrogen atoms are replaced by halogen atoms. Haloalkyl    includes both saturated alkyl groups and unsaturated alkenyl and    alkynyl groups, such as for example —CF₃, —CHF₂, —CH₂F, —CF₂CF₃,    —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃, —CF═CF₂,    —CCl═CH₂, —CBr═CH₂, —CI═CH₂, —C≡C—CF₃, —CHFCH₂CH₃ and —CHFCH₂CF₃.-   “Halogen” includes fluorine, chlorine, bromine and iodine atoms.-   “Heteroaryl” or “heteroaryl group” refers to (a) 5 and 6 membered    monocyclic aromatic rings, which contain, in addition to carbon    atom(s), at least one heteroatom, such as nitrogen, oxygen or    sulfur, and (b) 7-15 membered bicyclic and tricyclic rings, which    contain, in addition to carbon atom(s), at least one heteroatom,    such as nitrogen, oxygen or sulfur, and in which at least one of the    rings is aromatic. Heteroaryl groups can be substituted or    unsubstituted, and may be bridged, spiro, and/or fused. Examples    include, but are not limited to, 2,3-dihydrobenzofuranyl,    1,2-dihydroquinolinyl, 3,4-dihydroisoquinolinyl,    1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,    benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl,    3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,    oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or    5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl,    pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thienyl, 2-thienyl,    3-thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl,    triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl,    pyridazin-4-yl, pyrazin-2-yl, naphthyridinyl, pteridinyl,    phthalazinyl, purinyl, alloxazinyl, benzimidazolyl, benzofuranyl,    benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl,    benzothiazolyl, benzothiophenyl, benzoxazolyl, cinnolinyl,    furopyridinyl, indolinyl, indolizinyl, indolyl, or 2-, 3-, 4-, 5-,    6-, or 7-indolyl, 3H-indolyl, quinazolinyl, quinoxalinyl,    isoindolyl, isoquinolinyl,    10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienyl,    12-oxa-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienyl,    12-aza-tricyclo[7.2.1.0^(2,7)]dodeca-2(7),3,5-trienyl,    10-aza-tricyclo[6.3.2.0^(2,7)]trideca-2(7),3,5-trienyl,    2,3,4,5-tetrahydro-1H-benzo[d]azepinyl,    1,3,4,5-tetrahydro-benzo[d]azepin-2-onyl,    1,3,4,5-tetrahydro-benzo[b]azepin-2-onyl,    2,3,4,5-tetrahydro-benzo[c]azepin-1-onyl,    1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-onyl,    2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl,    5,6,8,9-tetrahydro-7-oxa-benzocycloheptenyl,    2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,    1,2,4,5-tetrahydro-benzo[e][1,3]diazepin-3-onyl,    3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,    3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-onyl,    6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl,    5,5-dioxo-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, and    2,3,4,5-tetrahydro-benzo[f][1,4]oxazepinyl. For example, a    heteroaryl group may contain 5, 6, or 8-15 ring atoms. As another    example, a heteroaryl group may contain 5 to 10 ring atoms, such as    5, 6, 9, or 10 ring atoms.-   “Heteroarylalkyl” or “heteroarylalkyl group” refers to an alkyl    group in which a hydrogen atom is replaced by a heteroaryl group,    wherein alkyl group and heteroaryl group are as previously defined    (i.e., heteroarylalkyl-). Heteroarylalkyl groups can be substituted    or unsubstituted. Examples include, but are not limited to, the    pyridinylmethyl isomers

-   “Heterocycloalkyl” or “heterocycloalkyl group” refers to 3-15    membered monocyclic, bicyclic, and tricyclic non-aromatic rings,    which may be saturated or unsaturated, can be substituted or    unsubstituted, may be bridged, spiro, and/or fused, and which    contain, in addition to carbon atom(s), at least one heteroatom,    such as nitrogen, oxygen, sulfur or phosphorus. Examples include,    but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl,    imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl,    piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl,    homomorpholinyl, homopiperidyl, homopiperazinyl,    thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, pyrrolidinyl,    tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl,    homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,    dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl,    dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,    tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide,    homothiomorpholinyl-5-oxide, quinuclidinyl,    2-oxa-5-azabicyclo[2.2.1]heptanyl,    8-oxa-3-aza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl,    2,5-diaza-bicyclo[2.2.1]heptanyl, 3,8-diaza-bicyclo[3.2.1]octanyl,    3,9-diaza-bicyclo[4.2.1]nonanyl, 2,6-diaza-bicyclo[3.2.2]nonanyl,    [1,4]oxaphosphinanyl-4-oxide, [1,4]azaphosphinanyl-4-oxide,    [1,2]oxaphospholanyl-2-oxide, phosphinanyl-1-oxide,    [1,3]azaphospholidinynl-3-oxide, [1,3]oxaphospholanyl-3-oxide and    7-oxabicyclo[2.2.1]heptanyl. A heterocycloalkyl group may contain,    in addition to carbon atom(s), at least one nitrogen, oxygen, or    sulfur. For example, a heterocycloalkyl group may contain, in    addition to carbon atom(s), at least one nitrogen or oxygen. A    heterocycloalkyl group may contain, in addition to carbon atom(s),    at least one nitrogen. A heterocycloalkyl group may contain carbon    atoms and 1 or 2 nitrogen atoms. A heterocycloalkyl group may    contain carbon atoms and an oxygen atom. A heterocycloalkyl group    may contain carbon atoms, a nitrogen atom, and an oxygen atom. A    heterocycloalkyl group may contain carbon atoms, a nitrogen atom,    and a sulfur atom. A heterocycloalkyl group may contain carbon atoms    and a sulfur atom. A heterocycloalkyl group may contain from 3 to 10    ring atoms. A heterocycloalkyl group may contain from 3 to 7 ring    atoms. A heterocycloalkyl group may contain from 5 to 7 ring atoms,    such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Unless    otherwise indicated, the foregoing heterocycloalkyl groups can be    C-attached or N-attached where such is possible and results in the    creation of a stable structure. For example, piperidinyl can be    piperidin-1-yl (N-attached) or piperidin-4-yl (C-attached).-   “Heterocycloalkylene” or “heterocycloalkylene group” refers to    diradical, 3-15 membered monocyclic, bicyclic, or tricyclic    non-aromatic ring systems, which may be saturated or unsaturated,    can be substituted or unsubstituted, may be bridged, spiro, and/or    fused, and which contain, in addition to carbon atom(s), at least    one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus.    Examples include, but are not limited to, the azridinylene isomers

The heterocycloalkylene group may contain, in addition to carbonatom(s), at least one nitrogen, oxygen, or sulfur. Theheterocycloalkylene group may contain, in addition to carbon atom(s), atleast one nitrogen or oxygen. The heterocycloalkylene group may contain,in addition to carbon atom(s), at least one nitrogen. For example, aheterocycloalkylene group may contain from 3 to 10 ring atoms; such asfrom 3 to 7 ring atoms. A heterocycloalkylene group may contain from 5to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.Unless otherwise indicated, the foregoing heterocycloalkylene groups canbe C-attached and/or N-attached where such is possible and results inthe creation of a stable structure. A heterocycloalkylene group can alsoinclude ring systems substituted on ring carbons with one or more —OHfunctional groups (which may further tautomerize to give a ring C═Ogroup) and/or substituted on a ring sulfur atom by one (1) or two (2)oxygen atoms to give S═O or SO₂ groups, respectively, and/or substitutedon a ring phosphorus by an oxygen atom to give P═O.

-   “Heterocycloalkylalkyl” or “heterocycloalkylalkyl group” refers to    an alkyl group in which a hydrogen atom is replaced by a    heterocycloalkyl group, wherein alkyl group and heterocycloalkyl    group are as previously defined (i.e., heterocycloalkylalkyl-).    Heteroycloalkylalkyl groups can be substituted or unsubstituted.    Examples include, but are not limited to, pyrrolidinylmethyl    (C₄H8NCH₂—).-   “Pharmaceutically acceptable” refers to physiologically tolerable    materials, which do not typically produce an allergic or other    untoward reaction, such as gastric upset, dizziness and the like,    when administered to a human.-   “Pharmaceutical composition” refers to a composition that can be    used to treat a disease, condition, or disorder in a human.-   “Pseudohalogen” refers to —OCN, —SCN, —CF₃, and —CN.-   “Stable” or “chemically stable” refers to a compound that is    sufficiently robust to be isolated to a useful degree of purity from    a reaction mixture. The present application is directed solely to    the preparation of stable compounds. When lists of alternative    substituents include members which, owing to valency requirements,    chemical stability, or other reasons, cannot be used to substitute a    particular group, the list is intended to be read in context to    include those members of the list that are suitable for substituting    the particular group. For example, R¹ can be C₁₋₆alkyl optionally    substituted by 1-13 R¹⁹; when R¹ is methyl, the methyl group is    optionally substituted by 1-3 R¹⁹.-   “Therapeutically effective amount” refers to an amount of a compound    sufficient to inhibit, halt, or cause an improvement in a disorder    or condition being treated in a particular subject or subject    population. For example in a human or other mammal, a    therapeutically effective amount can be determined experimentally in    a laboratory or clinical setting, or may be the amount required by    the guidelines of the United States Food and Drug Administration, or    equivalent foreign agency, for the particular disease and subject    being treated. It should be appreciated that determination of proper    dosage forms, dosage amounts, and routes of administration is within    the level of ordinary skill in the pharmaceutical and medical arts.-   “Treatment” refers to the acute or prophylactic diminishment or    alleviation of at least one symptom or characteristic associated or    caused by a disorder being treated. For example,

treatment can include diminishment of several symptoms of a disorder orcomplete eradication of a disorder.

II. Compounds

The compounds of the present application are defined by the followingnumbered Embodiments. When a higher numbered Embodiment refers back tomultiple previous lower numbered Embodiments in the alternative andcontains a new limitation not present in the lower numbered Embodiments,the higher numbered Embodiment is intended to be an express descriptionof each and every one of the alternatives. For example, if Embodiment 2refers back to Embodiment 1 and contains a limitation not present inEmbodiment 1, Embodiment 3 refers back Embodiments 1 or 2 and contains alimitation(s) not present in Embodiments 1 or 2, and Embodiment 4 refersback to any of Embodiments 1-3 and contains a limitation(s) not presentin Embodiments 1, 2, or 3, then Embodiment 4 is intended to be anexplicit description of a genus having the limitations of Embodiments 1and 4, an explicit description of a genus having the limitations ofEmbodiments 2 and 4 (i.e., 1, 2, and 4), and an explicit description ofa genus having the limitations of Embodiments 3 and 4 (i.e., 1, 3, and4, and 1, 2, 3 and 4). By way of example, if Embodiment 1 is a compoundof formula (I) defining R⁷, R⁸ and R⁹ independently as alkyl or aryl,Embodiment 2 is a compound of Embodiment 1 defining R⁷ as alkyl,Embodiment 3 is a compound of Embodiments 1 or 2 defining R⁸ as alkyl,and Embodiment 4 is a compound of any of Embodiments 1-3 defining R⁹ asalkyl, then Embodiment 4 is an explicit description of a genus havingthe limitations of Embodiments 1 and 4 (i.e., a compound of formula (I)in which R⁷ and R⁸ are alkyl or aryl, and R⁹ is alkyl), an explicitdescription of a genus having the limitations of Embodiments 2 and 4(i.e., a compound of formula (I) in which R⁸ is alkyl or aryl, and R⁷and R⁹ are alkyl), an explicit description of a genus having thelimitations of Embodiments 3 and 4 (i.e., a compound of formula (I) inwhich R⁷ is alkyl or aryl, and R⁸ and R⁹ are alkyl; and a compound offormula (I) in which R⁷, R⁸ and R⁹ are all alkyl). It should be noted inthis regard that when a higher numbered Embodiment refers to a lowernumbered Embodiment and contains limitations for a group(s) not presentin the lower numbered Embodiment, the higher numbered Embodiment shouldbe interpreted in context to ignore the missing group(s). For example,if Embodiment 1 recites a compound of formula (I) in which X is H,C₁₋₁₀alkyl, or —C(═O)R²⁸, Embodiment 2 recites a compound of Embodiment1 in which X is H or C₁₋₁₀alkyl, and Embodiment 3 recites a compound ofEmbodiments 1 or 2 in which R²⁸ is alkyl, then Embodiment 3 defines agenus having the limitations of Embodiments 1 and 3 and a genus havingthe limitation of Embodiments 2 and 3 (i.e., 1, 2, and 3). In the genusdefined by the limitations of Embodiments 2 and 3, X cannot be—C(═O)R²⁸; therefore this genus should be interpreted to ignore theEmbodiment 3 definition of R²⁸=alkyl (i.e., the genus of Embodiments 2and 3 has the same scope as the genus of Embodiment 2).

The compounds of the present application are defined herein usingstructural formulas that do not specifically recite the mass numbers orthe isotope ratios of the constituent atoms. It is intended that thepresent application includes compounds in which the constituent atomsare present in any ratio of isotope forms. For example, carbon atoms maybe present in any ratio of ¹²C, ¹³C, and ¹⁴C; hydrogen atoms may bepresent in any ratio of ¹H, ²H, and ³H; etc. Preferably, the constituentatoms in the compounds of the present application are present in theirnaturally occurring ratios of isotope forms.

Embodiment 1. A compound of formula (I)

or a salt formthereof,wherein

G is a group of formula

-   -   X is chosen from H, C₁₋₁₀alkyl optionally substituted by 1-13        R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁸, —C(═O)OR²⁸, —C(═O)NR²⁴R²⁸,        —C(═O)C(═O)R²⁸, —NR²⁴R²⁸, —NR²⁴NR²⁴R²⁸, N═NR²⁸ —NR²⁴OR²⁸,        —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)C(═O)R²⁸, —NR²⁴C(═O)OR²⁸,        —NR²⁴C(═O)C(═O)OR²⁸, —NR²⁴C(═O)NR²⁴R²⁸, —NR²⁴C(═O)NR²⁴C(═O)R²⁸,        NR²⁴C(═O)NR²⁴C(═O)OR²⁸, —NR²⁴C(═O)C(═O)NR²⁴R²⁸, —NR²⁴S(═O)₂R²⁸,        —NR²⁴S(═O)₂NR²⁴R²⁸, —OR²⁸, —OC(═O)R²⁸, —OC(═O)NR²⁴R²⁸,        —OC(═O)OR²⁸, —OS(═O)R²⁸, —OS(═O)₂R²⁸, —OS(═O)₂OR²⁸,        —OS(═O)₂NR²⁴R²⁸, —S(═O)_(n)R²⁸, —S(═O)₂NR²⁴R²⁸, and        —S(═O)NR²⁴R²⁸;    -   R⁷, R⁸, R⁹, R¹², R¹³, R¹⁴, R¹⁵, R^(a), R^(b), R^(c), R^(d),        R^(e), R^(f), R^(g), and R^(h) are independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11        R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³,        —(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰, —C(═NR²⁵)NR²²R²³, —C(═NOH)NR²²R²³,        —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰, —C(═NNR²⁴C(═O)R²¹)R²⁰,        —C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂, —NR²²R²³,        —NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,        —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,        —NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰,        —NR²⁴C(═O)NR²⁴C(═O)OR²⁰, —NR²⁴C(═NR²⁵)NR²²R²³,        —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰, —NR²⁴C(═S)OR²⁰,        —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,        —NR²⁴P(═O)R⁷⁸R⁷⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³),        —NR²⁴P(═)(OR²⁰)(OR²⁰), —NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN,        —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³,        —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³,        —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR²²R²³)(NR²²R²³), OP(═O)(OR²⁰)(OR²⁰),        —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰, —S(═O)₂R²⁰,        —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —SP(═O)R⁷⁸R⁷⁸,        —SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰),        —SP(═O)(SR²⁰)(SR²⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²R²³)(NR²²R²³),        —P(═O)(OR²⁰)(OR²⁰), and —P(═O)(SR²⁰)(SR²⁰);        -   or any of R⁷ and R⁸, R¹² and R¹³, R¹⁴ and R¹⁵, R^(a) and            R^(b), R^(a) and R^(e), R^(a) and R^(e), R^(a) and R^(g),            R^(b) and R^(d), R^(b) and R^(f), R^(b) and R^(h), R^(c) and            R^(d), R^(c) and R^(e), R^(c) and R^(g), R^(d) and R^(f),            R^(d) and R^(h), R^(e) and R^(f), R^(e) and R^(g), R^(f) and            R^(h), and R^(g) and R^(h) can, together with the atoms            linking them, form a C₆₋₁₁aryl optionally substituted by            1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21            R¹⁹, 3-15 membered heterocycloalkyl optionally substituted            by 1-28 R¹⁹ or a 5-15 membered heteroaryl optionally            substituted by 1-15 R¹⁹;    -   R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R³⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R³⁹, C₂₋₆alkynyl optionally substituted by        1-9 R³⁹, C₆₋₁₁aryl optionally substituted by 1-11 R³⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R³⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R³⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R³⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R³⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R³⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R³⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R³⁹, halogen, —CN, —C(═O)R³⁰, —C(═O)OR³⁰, —C(═O)NR³²R³³,        —C(═O)C(═O)R³⁰, —C(═NR³⁵)R³⁰, —C(═NR³⁵)NR³²R³³, —C(═NOH)NR³²R³³,        —C(═NOR³⁶)R³⁰, —C(═NNR³²R³³)R³⁰, —C(═NNR³⁴C(═O)R³¹)R³⁰,        —C(═NNR³⁴C(═O)OR³¹)R³⁰, —C(═S)NR³²R³³, —NC, —NO₂, —NR³²R³³,        —NR³⁴NR³²R³³, —N═NR³⁴, ═NR³⁰, ═NOR³⁰, —NR³⁴OR³⁶, —NR³⁴C(═O)R³⁰,        NR³⁴C(═O)C(═O)R³⁰, —NR³⁴C(═O)OR³¹, —NR³⁴C(═O)C(═O)OR³¹,        —NR³⁴C(═O)NR³²R³³, —NR³⁴C(═O)NR³⁴C(═O)R³⁰,        —NR³⁴C(═O)NR³⁴C(═O)OR³⁰, NR³⁴C(═NR³⁵)NR³²R³³,        —NR³⁴C(═O)C(═O)NR³²R³³, —NR³⁴C(═S)R³⁰, —NR³⁴C(═S)OR³⁰,        NR³⁴C(═S)NR³²R³³, —NR³⁴S(═O)₂R³¹, NR³⁴S(═O)₂NR³²R³³,        NR³⁴P(═O)R⁷⁸R⁷⁸, —NR³⁴P(═O)(NR³²R³³)(NR³²R³³),        —NR³⁴P(═O)(OR³⁰)(OR³⁰), —NR³⁴P(═O)(SR³⁰)(SR³⁰), —OR³⁰, ═O, —OCN,        —OC(═O)R³⁰, —OC(═O)NR³²R³³, —OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³,        —OS(═O)R³⁰, —OS(═O)₂R³⁰, —OS(═O)₂OR³⁰, —OS(═O)₂NR³²R³³,        —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR³²R³³)(NR³²R³³), —OP(═O)(OR³⁰)(OR³⁰),        —OP(═O)(SR³⁰)(SR³⁰), —Si(R³⁴)₃, —SCN, ═S, —S(═O)_(n)R³⁰,        —S(═O)₂OR³⁰, —SO₃R³⁷, —S(═O)₂NR³²R³³, —S(═O)NR³²R³³,        —SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR³²R³²R)(NR³²R³³), —SP(═O)(OR³⁰)(OR³⁰),        —SP(═O)(SR³⁰)(SR³⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR³²R³³)(NR³²R³³),        —P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰);

R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R⁴⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁴⁹,C₂₋₆alkynyl optionally substituted by 1-9 R⁴⁹, C₆₋₁₁aryl optionallysubstituted by 1-11 R⁴⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R⁴⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁴⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁴⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R⁴⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R⁴⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R⁴⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R⁴⁹;

-   -   R²⁸ at each occurrence is independently chosen from C₁₋₁₀alkyl        optionally substituted by 1-13 R⁴⁹, C₂₋₁₀alkenyl optionally        substituted by 1-11 R⁴⁹, C₂₋₆alkynyl optionally substituted by        1-9 R⁴⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁴⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁴⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁴⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁴⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁴⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁴⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁴⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁴⁹;    -   R²², R²³, R³² and R³³ at each occurrence is independently chosen        from H, C₁₋₆alkyl optionally substituted by 1-13 R⁵⁹,        C₂₋₆alkenyl optionally substituted by 1-11 R⁵⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R⁵⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R⁵⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁵⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁵⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁵⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁵⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁵⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁵⁹;        -   or any R²² and R²³ and/or R³² and R³³ may form, together            with the nitrogen atom to which they are attached, a 3-15            membered heterocycloalkyl optionally substituted by 1-28 R⁶⁹            or a 5-15 membered heteroaryl optionally substituted by 1-15            R⁶⁹;

R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-13 R⁷⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R⁷⁹, C₂₋₆alkynyl optionally substituted by 1-9 R⁷⁹,C₆₋₁₁aryl optionally substituted by 1-11 R⁷⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R⁷⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R⁷⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁷⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R⁷⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R⁷⁹, 5-15membered heteroaryl optionally substituted by 1-15 R⁷⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R⁷⁹, halogen, —CN,—C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —C(═O)C(═O)R⁷⁰, —C(═NR⁷⁵)R⁷⁰,—C(═NR⁷⁵)NR⁷²R⁷³, —C(═NOH)NR⁷²R⁷³, —C(═NOR⁷⁶)R⁷⁰, —C(═NNR⁷²R⁷³)R⁷⁰,—C(═NNR⁷⁴C(═O)R⁷¹)R⁷⁰, —C(═NNR⁷⁴C(═O)OR⁷¹)R⁷⁰, —C(═S)NR⁷²R⁷³, —NC, —NO₂,—NR⁷²R⁷³, —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, ═NR⁷⁰, ═NOR⁷⁰, —NR⁷⁴OR⁷⁶,—NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)C(═O)R⁷⁰, —NR⁷⁴C(═)OR⁷¹, —NR⁷⁴C(═O)C(═O)OR⁷¹,—NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰, NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰,NR⁷⁴C(═NR⁷⁵)NR⁷²R⁷³, —NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —NR⁷⁴C(═S)R⁷⁰,—NR⁷⁴C(═S)OR⁷⁰, —NR⁷⁴C(═S)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³,—NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —NR⁷⁴P(═O)(OR⁷⁰)(OR⁷⁰),—NR⁷⁴P(═O)(SR⁷⁰)(SR⁷⁰), —OR⁷⁰, ═O, —OCN, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³,—OC(═O)OR⁷⁰, —OC(═NR⁷⁵)NR⁷²R⁷³, —OS(═O)R⁷⁰, —OS(═O)₂R⁷⁰, —OS(═O)₂R⁷⁰,—OS(═O)₂NR⁷²R⁷³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),—OP(═O)(OR⁷⁰)(OR⁷⁰), —OP(═O)(SR⁷⁰)(SR⁷⁰), —Si(R⁷⁴)₃, —SCN, ═S,—S(═O)_(n)R⁷⁰, —S(═O)₂OR⁷⁰, —SO₃R, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,—SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),—SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),—P(═O)(OR⁷⁰)(OR⁷⁰), and —P(═O)(SR⁷⁰)(SR⁷⁰);

-   -   R⁷⁰, R⁷¹, R⁷⁴, R⁷, R⁷⁶ and R⁷⁷ at each occurrence is        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R⁸⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁸⁹,        C₂₋₆alkynyl optionally substituted by 1-9 R⁸⁹, C₆₋₁₁aryl        optionally substituted by 1-11 R⁸⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-19 R⁸⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-21 R⁸⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32        R⁸⁹, 3-15 membered heterocycloalkyl optionally substituted by        1-28 R⁸⁹, 4-21 membered heterocycloalkylalkyl optionally        substituted by 1-40 R⁸⁹, 5-15 membered heteroaryl optionally        substituted by 1-15 R⁸⁹, and 6-21 membered heteroarylalkyl        optionally substituted by 1-27 R⁸⁹;    -   R⁷² and R⁷³ at each occurrence is independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R⁹⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R⁹⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R⁹⁹, C₆₋₁₁aryl optionally substituted by 1-11        R⁹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁹⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁹⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁹⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁹⁹;        -   or any R⁷² and R⁷³ may form, together with the nitrogen atom            to which they are attached, a 3-15 membered heterocycloalkyl            optionally substituted by 1-28 R¹⁰⁹ or a 5-15 membered            heteroaryl optionally substituted by 1-15 R¹⁰⁹;    -   R⁷⁸ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R⁸⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R⁸⁹, C₂₋₆alkynyl optionally substituted by        1-9 R⁸⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁸⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁸⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁸⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁸⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁸⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁸⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁸⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27R⁸⁹;        -   or any two R⁷⁸ attached to the same phosphorus atom can,            together with the phosphorus atom linking them, form a 3-10            membered heterocycloalkyl optionally substituted by 1-6 R⁸⁹;    -   R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently        chosen from C₁₋₆alkyl optionally substituted by 1-13 R¹¹⁹,        C₂₋₆alkenyl optionally substituted by 1-11 R¹¹⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R¹¹⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R¹¹⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R¹¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21        R¹¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹¹⁹,        3-15 membered heterocycloalkyl optionally substituted by 1-28        R¹¹⁹, 4-21 membered heterocycloalkylalkyl optionally substituted        by 1-40 R¹¹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹¹⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹¹⁹, halogen, —CN, —C(═O)R¹¹⁰, —C(═O)OR¹¹⁰,        —C(═O)NR¹¹²R¹¹³, —C(═O)C(═O)R¹¹⁰, —C(═NR¹¹⁵)R¹¹⁰,        —C(═NR¹¹⁵)NR¹¹²R¹¹³, —C(═NOH)NR¹¹²R¹¹³, —C(═NOR¹¹⁶)R¹¹⁰,        —C(═NNR¹¹²R¹¹³)R¹¹⁰, —C(═NNR¹¹⁴C(═O)R¹¹¹)R¹¹⁰,        —C(═NNR¹¹⁴C(═O)OR¹¹¹)R¹¹⁰, —C(═S)NR¹¹²R¹¹³, —NC, —NO₂,        —NR¹¹²R¹¹³, —NR¹¹⁴NR¹¹²R¹¹³, —N═NR¹¹⁴, ═NR¹¹⁰, ═NOR¹¹⁰,        —NR¹¹⁴OR¹¹⁶, —NR¹¹⁴C(═O)R¹¹⁰, —NR¹¹⁴C(═O)C(═O)R¹¹⁰,        —NR¹¹⁴C(═O)OR¹¹¹, —NR¹¹⁴C(═O)C(═O)OR¹¹¹, —NR¹¹⁴C(═O)NR¹¹²R¹¹³,        —NR¹¹⁴C(═O)NR¹¹⁴C(═O)R¹¹⁰, —NR¹¹⁴C(═O)NR¹¹⁴C(═O)OR¹¹⁰,        —NR¹¹⁴C(═NR¹¹⁵)NR¹¹²R¹¹³, —NR¹¹⁴C(═O)C(═O)NR¹¹²R¹¹³,        —NR¹¹⁴C(═S)R¹¹⁰, —NR¹¹⁴C(═S)OR¹¹⁰, —NR¹¹⁴C(═S)NR¹¹²R¹¹³,        —NR¹¹⁴S(═O)₂R¹¹, —NR¹¹⁴S(═O)₂NR¹¹²R¹¹³, —NR¹¹⁴P(═O)R¹¹⁸R¹¹⁸,        —NR¹¹⁴P(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³),        —NR¹¹⁴P(═O)(OR¹¹⁰)(OR¹¹⁰)—NR¹¹⁴P(═O)(SR¹¹⁰)(SR¹¹⁰), —OR¹¹⁰, ═O,        —OCN, —OC(═O)R¹¹⁰, —OC(═O)NR¹¹²R¹¹³, —OC(═O)OR¹¹⁰,        —OC(═NR¹¹⁵)NR¹¹²R¹¹³, —OS(═O)R¹¹⁰, —OS(═O)₂R¹¹⁰, —OS(═O)₂OR¹¹⁰,        —OS(═O)₂NR¹¹²R¹¹³, —OP(═O)R¹¹⁸R¹¹⁸,        —OP(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³), —OP(═O)(OR¹¹⁰)(OR¹¹⁰),        —OP(═O)(SR¹¹⁰)(SR¹¹⁰), —Si(R¹¹⁴)₃, —SCN, ═S, —S(═O)_(n)R¹¹⁰,        —S(═O)₂OR¹¹⁰, —SO₃R¹¹¹¹, —S(═O)₂NR¹¹²R¹¹³, —S(═O)NR¹¹²R¹¹³,        —SP(═O)R¹¹⁸R¹¹⁸, —SP(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³),        —SP(═O)(OR¹¹⁰)(OR¹¹⁰), —SP(═O)(SR¹¹⁰)(SR¹¹⁰), —P(═O)R¹¹⁸R¹¹⁸,        —P(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³), —P(═O)(OR¹¹⁰)(OR¹¹⁰), and        —P(═O)(SR¹¹⁰)(SR¹¹⁰);    -   R¹¹⁰, R¹¹¹, R¹¹⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence is        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R¹²⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹²⁹,        C₂₋₆alkynyl optionally substituted by 1-9 R¹²⁹, C₆₋₁₁aryl        optionally substituted by 1-11 R¹²⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-19 R¹²⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-21 R¹²⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by        1-32 R¹²⁹, 3-15 membered heterocycloalkyl optionally substituted        by 1-28 R¹²⁹, 4-21 membered heterocycloalkylalkyl optionally        substituted by 1-40 R¹²⁹, 5-15 membered heteroaryl optionally        substituted by 1-15 R¹²⁹, and 6-21 membered heteroarylalkyl        optionally substituted by 1-27 R¹²⁹;    -   R¹¹² and R¹¹³ at each occurrence is independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R¹³⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R¹³⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R¹³⁹, C₆₋₁₁aryl optionally substituted by        1-11 R¹³⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹³⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹³⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹³⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹³⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹³⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹³⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R³⁹;        -   or any R¹¹² and R¹¹³ may form, together with the nitrogen            atom to which they are attached, a 3-15 membered            heterocycloalkyl optionally substituted by 1-28 R¹⁴⁹ or a            5-15 membered heteroaryl optionally substituted by 1-15 R¹⁴⁹    -   R¹¹⁸ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R¹²⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R¹²⁹, C₂₋₆alkynyl optionally substituted by        1-9 R¹²⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹²⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹²⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹²⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹²⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹²⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹²⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹²⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R¹²⁹;    -   R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independently        chosen from C₁₋₆alkyl optionally substituted by 1-13 R¹⁵⁹,        C₂₋₆alkenyl optionally substituted by 1-11 R¹⁵⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R¹⁵⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R¹⁵⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R¹⁵⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21        R¹⁵⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁵⁹,        3-15 membered heterocycloalkyl optionally substituted by 1-28        R¹⁵⁹, 4-21 membered heterocycloalkylalkyl optionally substituted        by 1-40 R¹⁵⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁵⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹⁵⁹, halogen, —CN, —C(═O)R¹⁵⁰, —C(═O)OR¹⁵⁰,        C(═O)NR¹⁵²R¹⁵³, —C(═O)C(═O)R¹⁵⁰, —C(═NR¹⁵⁵)R¹⁵⁰,        —C(═NR¹⁵⁵)NR¹⁵²R¹⁵³, —C(═NOH)NR¹⁵²R¹⁵³, —C(═NOR¹⁵⁶)R¹⁵⁰,        —C(═NNR¹⁵²R¹⁵³)R¹⁵⁰, —C(═NNR¹⁵⁴C(═O)R¹⁵¹)R¹⁵⁰,        —C(═NNR¹⁵⁴C(═O)OR¹⁵¹)R¹⁵⁰, —C(═S)NR¹⁵²R¹⁵³, —NC, —NO₂,        —NR¹⁵²R¹⁵⁰, —NR¹⁵⁴NR¹⁵²R¹⁵³, —N═NR¹⁵⁴, ═NR¹⁵⁰, ═NOR¹⁵,        —NR¹⁵⁴OR¹⁵⁶, —NR¹⁵⁴C(═O)R¹⁵⁰, —NR¹⁵⁴C(═O)C(═O)R¹⁵⁰,        —NR¹⁵⁴C(═)OR¹⁵¹, —NR¹⁵⁴C(═O)C(═O)OR¹⁵¹, —NR¹⁵⁴C(═O)NR¹⁵²R¹⁵³,        —NR¹⁵⁴C(═O)NR¹⁵⁴C(═O)R¹⁵⁰, —NR¹⁵⁴C(═O)NR¹⁵⁴C(═O)OR¹⁵⁰,        —NR¹⁵⁴C(═NR¹⁵⁵)NR¹⁵²R¹⁵³, NR¹⁵⁴C(═O)C(═O)NR¹⁵²R¹⁵³,        NR¹⁵⁴C(═S)R¹⁵⁰, —NR¹⁵⁴C(═S)OR¹⁵⁰, —NR¹⁵⁴C(═S)NR¹⁵²R¹⁵³,        NR¹⁵⁴S(═O)₂R¹⁵¹, NR¹⁵⁴S(═O)₂NR¹⁵²R¹⁵³, —NR¹⁵⁴P(═O)R¹⁵⁸R¹⁵⁸,        —NR¹⁵⁴P(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³), —NR¹⁵⁴P(═O)(OR¹⁵⁰)(OR¹⁵⁰),        —NR¹⁵⁴P(═O)(SR¹⁵⁰)(SR¹⁵⁰), —OR¹⁵⁰, ═O, —OCN, —OC(═O)R¹⁵⁰,        —OC(═O)NR¹⁵²R¹⁵³, —OC(═)OR¹⁵⁰, —OC(═NR¹⁵⁵)NR¹⁵²R¹⁵³,        —OS(═O)R¹⁵⁰, —OS(═O)₂R¹⁵⁰, —OS(═O)₂OR¹⁵, —OS(═O)₂NR¹⁵²R¹⁵³,        —OP(═O)R¹⁵⁸R¹⁵⁸, —OP(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³),        —OP(═O)(OR¹⁵⁰)(OR¹⁵⁰), —OP(═O)(SR¹⁵⁰)(SR¹⁵⁰),—Si(R¹⁵⁴)₃, —SCN,        ═S, —S(═O)_(n)R¹⁵⁰, —S(═O)₂OR¹⁵⁰, —SO₃R¹⁵¹⁵, —S(═O)₂NR¹⁵²R¹⁵³,        —S(═O)NR¹⁵²R¹⁵³, —SP(═O)R¹⁵⁸R¹⁵⁸, —SP(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³),        —SP(═O)(OR¹⁵⁰)(OR¹⁵⁰), —SP(═O)(SR¹⁵⁰)(SR¹⁵⁰), —P(═O)R¹⁵⁸R¹⁵⁸,        —P(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³), —P(═O)(OR¹⁵⁰)(OR¹⁵⁰), and        —P(═O)(SR¹⁵⁰)(SR¹⁵⁰);    -   R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence is        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R¹⁶⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁶⁹,        C₂₋₆alkynyl optionally substituted by 1-9 R¹⁶⁹, C₆₋₁₁aryl        optionally substituted by 1-11 R¹⁶⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-19 R¹⁶⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-21 R¹⁶⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by        1-32 R¹⁶⁹, 3-15 membered heterocycloalkyl optionally substituted        by 1-28 R¹⁶⁹, 4-21 membered heterocycloalkylalkyl optionally        substituted by 1-40 R¹⁶⁹, 5-15 membered heteroaryl optionally        substituted by 1-15 R¹⁶⁹, and 6-21 membered heteroarylalkyl        optionally substituted by 1-27 R¹⁶⁹;    -   R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R¹⁷⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R¹⁷⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R¹⁷⁹, C₆₋₁₁aryl optionally substituted by        1-11 R¹⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁷⁹,        C₃₋₁₁ cycloalkyl optionally substituted by 1-21 R¹⁷⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁷⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁷⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹⁷⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁷⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R¹⁷⁹;        -   or any R¹⁵² and R¹⁵³ may form, together with the nitrogen            atom to which they are attached, a 3-15 membered            heterocycloalkyl optionally substituted by 1-28 R¹⁸⁹ or a            5-15 membered heteroaryl optionally substituted by 1-15            R¹⁸⁹;    -   R¹⁵⁸ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R¹⁶⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R¹⁶⁹, C₂₋₆alkynyl optionally substituted by        1-9 R¹⁶⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁶⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁶⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁶⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁶⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁶⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹⁶⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁶⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁶⁹;    -   R¹⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independently        chosen from C₁₋₆alkyl optionally substituted by 1-13 R¹⁹⁹,        C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R¹⁹⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R¹⁹⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R¹⁹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21        R¹⁹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹⁹,        3-15 membered heterocycloalkyl optionally substituted by 1-28        R¹⁹⁹, 4-21 membered heterocycloalkylalkyl optionally substituted        by 1-40 R¹⁹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁹⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹⁹⁹, halogen, —CN, —C(═O)R¹⁹⁰, —C(═O)OR¹⁹⁰,        —C(═O)NR¹⁹²R¹⁹³, —C(═O)C(═O)R¹⁹⁰, —C(═NR¹⁹⁵)R¹⁹⁰,        —C(═NR¹⁹⁵)NR¹⁹²R¹⁹³, —C(═NOH)NR¹⁹²R¹⁹³, —C(═NOR¹⁹⁶)R¹⁹⁰,        —C(═NNR¹⁹²R¹⁹³)R¹⁹⁰, —C(═NNR¹⁹⁴C(═O)R¹⁹¹)R¹⁹⁰,        —C(═NNR¹⁹⁴C(═O)OR¹⁹¹)R¹⁹⁰, —C(═S)NR¹⁹²R¹⁹³, —NC, —NO₂,        —NR¹⁹²R¹⁹³, —NR¹⁹⁴NR¹⁹²R¹⁹³, —N═NR¹⁹⁴, ═NR¹⁹⁰, ═NOR¹⁹⁰,        —NR¹⁹⁴OR¹⁹⁶, —NR¹⁹⁴C(═O)R¹⁹⁰, —NR¹⁹⁴C(═O)C(═O)R¹⁹⁰,        —NR¹⁹⁴C(═O)OR¹⁹¹, —NR¹⁹⁴C(═O)C(═O)OR¹⁹¹, —NR¹⁹⁴C(═O)NR¹⁹²R¹⁹³,        —NR¹⁹⁴C(═O)NR¹⁹⁴C(═O)R¹⁹⁰, —NR¹⁹⁴C(═O)NR¹⁹⁴C(═)OR¹⁹⁰,        —NR¹⁹⁴C(═NR¹⁹⁵)NR¹⁹²R¹⁹³, —NR¹⁹⁴C(═O)C(═O)NR¹⁹²R¹⁹³,        NR¹⁹⁴C(═S)R¹⁹⁰, —NR¹⁹⁴C(═S)OR¹⁹⁰, NR¹⁹⁴C(═S)NR¹⁹²R¹⁹³,        —NR¹⁹⁴S(═O)₂R¹⁹¹, —NR¹⁹⁴S(═O)₂NR¹⁹²R¹⁹²R¹⁹³,        —NR¹⁹⁴P(═O)R¹⁹⁸R¹⁹⁸,        —NR¹⁹⁴P(═O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³)—NR¹⁹⁴P(═)(OR¹⁹⁰)(OR¹⁹⁰),—NR¹⁹⁴P(═O)(SR¹⁹⁰)(SR¹⁹⁰)—OR¹⁹⁰,        ═O, —OCN, —OC(═O)R¹⁹⁰, —OC(═O)NR¹⁹²R¹⁹³, —OC(═O)OR¹⁹⁰,        —OC(═NR¹⁹⁵)NR¹⁹²R¹⁹³, —OS(═O)R¹⁹⁰, —OS(═O)₂R¹⁹⁰, —OS(═O)₂OR¹⁹⁰,        —OS(═O)₂NR¹⁹²R¹⁹³, —OP(═O)R¹⁹⁸R¹⁹⁸,        —OP(═O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³), —OP(═O)(OR¹⁹⁰)(OR¹⁹⁰),        —OP(═O)(SR¹⁹⁰)(SR¹⁹⁰), —Si(R¹⁹⁴)₃, —SCN, ═S, —S(═O)_(n)R¹⁹⁰,        —S(═O)₂R¹⁹⁰, —SO₃R¹⁹¹⁹, —S(═O)₂NR¹⁹²R¹⁹³, —S(═O)NR¹⁹²R¹⁹³,        —SP(═O)R¹⁹⁸R¹⁹⁸, —SP(═O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³),        —SP(═O)(OR¹⁹⁰)(OR¹⁹⁰),—SP(═O)(SR¹⁹⁰)(SR¹⁹⁰),—P(═O)R¹⁹⁸R¹⁹⁸,        —P(═O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³), —P(═O)(OR¹⁹⁰)(OR¹⁹⁰), and        —P(═O)(SR¹⁹⁰)(SR¹⁹⁰);    -   R¹⁹⁰, R⁹¹, R⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence is        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R²⁰⁹, C₂₋₆alkenyl optionally substituted by 1-11 R²⁰⁹,        C₂₋₆alkynyl optionally substituted by 1-9 R²⁰⁹, C₆₋₁₁aryl        optionally substituted by 1-11 R²⁰⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-19 R²⁰⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-21 R²⁰⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by        1-32 R²⁰⁹, 3-15 membered heterocycloalkyl optionally substituted        by 1-28 R²⁰⁹, 4-21 membered heterocycloalkylalkyl optionally        substituted by 1-40 R²⁰⁹, 5-15 membered heteroaryl optionally        substituted by 1-15 R²⁰⁹, and 6-21 membered heteroarylalkyl        optionally substituted by 1-27 R²⁰⁹    -   R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R²¹⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R²¹⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R²¹⁹, C₆₋₁₁aryl optionally substituted by        1-11 R²¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R²¹⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R²¹⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R²¹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R²¹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R²¹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R²¹⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R²¹⁹;        -   or any R¹⁹² and R¹⁹³ may form, together with the nitrogen            atom to which they are attached, a 3-15 membered            heterocycloalkyl optionally substituted by 1-28 R²²⁹ or a            5-15 membered heteroaryl optionally substituted by 1-15            R²²⁹;    -   R¹⁹⁸ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R²⁰⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R²⁰⁹, C₂₋₆alkynyl optionally substituted by        1-9 R²⁰⁹, C₆₋₁₁aryl optionally substituted by 1-11 R²⁰⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R²⁰⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R²⁰⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R²⁰⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R²⁰⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R²⁰⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R²⁰⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R²⁰⁹    -   R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independently        chosen from C₁₋₆alkyl optionally substituted by 1-13 halogen,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₁aryl, C₇₋₁₆arylalkyl,        C₃₋₁₁cycloalkyl, C₄₋₁₇cycloalkylalkyl, 3-15 membered        heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15        membered heteroaryl, 6-21 membered heteroarylalkyl, halogen,        —CN, —C(═O)R²³⁰, —C(═)OR²³⁰, —C(═O)NR²³⁰R²³⁰, —C(═O)C(═O)R²³⁰,        —C(═NR²³⁰)R²³⁰,—C(═NR²³⁰)NR²³⁰R²³⁰, —C(═NOH)NR²³⁰R²³⁰,        —C(═NOR²³⁰)R²³⁰, —C(═NNR²³⁰R²³⁰)R²³⁰, —C(═NNR²³⁰C(═O)R²³⁰)R²³⁰,        —C(═NNR²³⁰C(═O)OR²³⁰)R²³⁰, —C(═S)NR²³⁰R²³⁰, —NC, —NO₂,        —NR²³⁰R²³⁰, —NR²³⁰NR²³⁰R²³⁰, —N═NR²³⁰, ═NR²³⁰, ═NOR²³⁰,        —NR²³⁰OR²³⁰, —NR²³⁰C(═O)R²³⁰, —NR²³⁰C(═O)C(═O)R²³⁰,        —NR²³⁰C(═O)OR²³⁰, —NR²³⁰C(═O)C(═O)OR²³⁰, —NR²³⁰C(═O)NR²³⁰R²³⁰,        —NR²³⁰C(═O)NR²³⁰C(═O)R²³⁰, —NR²³⁰C(═O)NR²³⁰C(═O)OR²³⁰,        —NR²³⁰C(═NR²³⁰)NR²³⁰R²³⁰, —NR²³⁰C(═O)C(═O)NR²³⁰R²³⁰,        —NR²³⁰C(═S)R²³⁰, —NR²³⁰C(═S)OR²³⁰, —NR²³⁰C(═S)NR²³⁰R²³⁰,        —NR²³⁰S(═)₂R²³⁰, —NR²³⁰S(═O)₂NR²³⁰R²³⁰, —NR²³⁰P(═O)R²³¹R²³¹,        —NR²³⁰P(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰), —NR²³⁰P(═O)(OR²³⁰)(OR²³⁰),        —NR²³⁰P(═O)(SR²³⁰)(SR²³⁰), —OR²³⁰, ═O, —OCN, —OC(═O)R²³⁰,        —OC(═O)NR²³⁰R²³⁰, —OC(═O)OR²³⁰, —OC(═NR²³⁰)NR²³⁰R²³⁰,        —OS(═O)R²³⁰, OS(═)₂R²³⁰, —OS(═O)₂OR²³⁰, —OS(═O)₂NR²³⁰R²³⁰,        —OP(═O)R²³¹R²³¹, —OP(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰),        —OP(═O)(OR²³⁰)(OR²³⁰), —OP(═O)(SR²³⁰)(SR²³⁰), —Si(R²³⁰)₃, —SCN,        ═S, —S(═O)_(n)R²³⁰, —S(═O)₂R²³⁰, —SO₃R²³⁰, —S(═O)₂NR²³⁰R²³⁰,        —S(═O)NR²³⁰R²³⁰, —SP(═O)R²³¹R²³¹, —SP(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰),        —SP(═O)(OR²³⁰)(OR²³⁰), —SP(═)(SR²³⁰)(SR²³⁰), —P(═O)R²³¹R²³¹,        —P(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰), —P(═O)(OR²³⁰)(OR²³⁰), and        —P(═O)(SR²³⁰)(SR²³⁰);

R²³⁰ at each occurrence is independently chosen from H, C₁₋₆alkyl andC₁₋₆-haloalkyl;

R²³¹ at each occurrence is independently chosen from C₁₋₆alkyl andC₁₋₆-haloalkyl; and n at each occurrence is independently chosen from 0,1, and 2;

with the proviso that the compound is not

in which D is H or

or a salt form thereof;

in which D is

or a salt form thereof; or

in which D is H or —CH₃, or a salt form thereof.

Embodiment 2

The compound of Embodiment 1, wherein G is a group of formula

Embodiment 3

The compound of Embodiment 1, wherein G is a group of formula

Embodiment 4

The compound of any of Embodiments 1-3, wherein X is chosen from H,C₁₋₁₀alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, —C(═O)R²⁸,—C(═O)OR²⁸, —C(═O)NR²⁴R²⁸, —C(═O)C(═O)R²⁸, —NR²⁴R²⁸, —NR²⁴NR²⁴R²⁸,—N═NR²⁸, —NR²⁴OR²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)C(═O)R²⁸, —NR²⁴C(═O)OR²⁸,—NR²⁴C(═O)C(═O)OR²⁸, —NR²⁴C(═O)NR²⁴R²⁸, —NR²⁴C(═O)NR²⁴C(═O)R²⁸,—NR²⁴C(═O)NR²⁴C(═O)OR²⁸, —NR²⁴C(═O)C(═O)NR²⁴R²⁸, —NR²⁴S(═O)₂R²⁸,—NR²⁴S(═O)₂NR²⁴R²⁸, —OR²⁸, —OC(═O)R²⁸, —OC(═O)NR²⁴R²⁸, —OC(═O)OR,—OS(═O)R²⁸, —OS(═O)₂R²⁸, —OS(═O)₂OR²⁸, —OS(═O)₂NR²⁴R²⁸, —S(═O)_(n)R²⁸,—S(═O)₂NR²⁴R²⁸, and —S(═O)NR²⁴R²⁸.

Embodiment 5

The compound of any of Embodiments 1-3, wherein X is chosen from H,C₁₋₁₀alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, —C(═O)R²⁸,—C(═O)OR²⁸, —C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)OR²⁸,—NR²⁴C(═O)NR²⁴R²⁸, —NR²⁴S(═O)₂R²⁸, —NR²⁴S(═O)₂NR²⁴R²⁸, —OR²⁸,—OC(═O)R²⁸, —OC(═O)NR²⁴R²⁸, —OS(═O)R²⁸, —OS(═O)₂R²⁸, —OS(═O)₂NR²⁴R²⁸,—S(═O)_(n)R²⁸, —S(═O)₂NR²⁴R²⁸, and —S(═O)NR²⁴R²⁸.

Embodiment 6

The compound of any of Embodiments 1-3, wherein X is chosen from H,C₁₋₁₀alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-6 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-6 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)OR²⁸, —C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)OR²⁸,—NR²⁴C(═O)NR²⁴R²⁸, —NR²⁴S(═O)₂R²⁸, —NR²⁴S(═O)₂NR²⁴R²⁸, —OR²⁸,—OC(═O)R²⁸, —OC(═O)NR²⁴R²⁸, —OS(═O)R²⁸, —OS(═O)₂R²⁸, —OS(═O)₂NR²⁴R²⁸,—S(═O)_(n)R²⁸, —S(═O)₂NR²⁴R²⁸, and —S(═O)NR²⁴R²⁸.

Embodiment 7

The compound of any of Embodiments 1-3, wherein X is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, C₄₋₇cycloalkylalkyl optionally substituted by 1-6 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 4-7membered heterocycloalkylalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, 6-11 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)OR²⁸, —C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)OR²⁸,—NR²⁴C(═O)NR²⁴R²⁸, —NR²⁴S(═O)₂R²⁸, —NR²⁴S(═O)₂NR²⁴R²⁸, —OR²⁸,—OC(═O)R²⁸, —OC(═O)NR²⁴R²⁸, —OS(═O)R²⁸, —OS(═O)₂R²⁸, —OS(═O)₂NR²⁴R²⁸,—S(═)_(n)R²⁸, —S(═O)₂NR²⁴R²⁸, and —S(═O)NR²⁴R²⁸.

Embodiment 8

The compound of any of Embodiments 1-3, wherein X is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, C₄₋₇cycloalkylalkyl optionally substituted by 1-6 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 4-7membered heterocycloalkylalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, 6-11 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸, —C(═)OR²⁸,—C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)NR²⁴R²⁸,—NR²⁴S(═O)₂R²⁸, —OR²⁸, —OC(═O)R²⁸, —S(═O)_(n)R²⁸, and —S(═O)₂NR²⁴R²⁸.

Embodiment 9

The compound of any of Embodiments 1-3, wherein X is chosen fromC₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, C₄₋₇cycloalkylalkyl optionally substituted by 1-6 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 4-7membered heterocycloalkylalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, 6-11 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)OR²⁸, —C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)OR²⁸,—NR²⁴C(═O)NR²⁴R²⁸, —NR²⁴S(═O)₂R²⁸, —NR²⁴S(═O)₂NR²⁴R²⁸, —OR²⁸,—OC(═O)R²⁸, —OC(═O)NR²⁴R²⁸, —OS(═O)R²⁸, —OS(═)₂R²⁸, —OS(═O)₂NR²⁴R²⁸,—S(═)_(n)R²⁸, —S(═O)₂NR²⁴R²⁸, and —S(═O)NR⁴R²⁸.

Embodiment 10

The compound of any of Embodiments 1-3, wherein X is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, C₄₋₇cycloalkylalkyl optionally substituted by 1-6 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 4-7membered heterocycloalkylalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, 6-11 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)OR²⁸, —C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)₂NR²⁴R²⁸,—NR²⁴S(═O)₂R²⁸, —OR²⁸, —OC(═O)R²⁸, —S(═O)_(n)R²⁸, and —S(═O)₂NR²⁴R²⁸.

Embodiment 11

The compound of any of Embodiments 1-3, wherein X is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)OR²⁸, —C(═O)NR⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)NR²⁴R²⁸,—NR²⁴S(═O)₂R²⁸, —OR²⁸, —OC(═O)R²⁸, —S(═O)_(n)R²⁸, and —S(═O)₂NR²⁴R²⁸.

Embodiment 12

The compound of any of Embodiments 1-3, wherein X is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)OR²⁸, —C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)NR²⁴R²⁸,NR²⁴S(═O)₂R²⁸, —OR²⁸, —OC(═O)R²⁸, —S(═O)_(n)R²⁸, and —S(═O)₂NR²⁴R²⁸.

Embodiment 13

The compound of any of Embodiments 1-3, wherein X is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴S(═O)₂R²⁸, and —OR²⁸.

Embodiment 14

The compound of any of Embodiments 1-3, wherein X is chosen from H, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴S(═O)₂R²⁸, and —OR²⁸.

Embodiment 15

The compound of any of Embodiments 1-3, wherein X is chosen fromC₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, C₄₋₇cycloalkylalkyl optionally substituted by 1-6 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 4-7membered heterocycloalkylalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, 6-11 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)OR²⁸, —C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)NR²⁴R²⁸,—NR²⁴S(═O)₂R²⁸, —OR²⁸, —OC(═O)R²⁸, —S(═O)_(n)R²⁸, and —S(═O)₂NR²⁴R²⁸.

Embodiment 16

The compound of any of Embodiments 1-3, wherein X is chosen fromC₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)OR²⁸, —C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)NR²⁴R²⁸,—NR²⁴S(═O)₂R²⁸, —OR²⁸, —OC(═O)R²⁸, —S(═O)_(n)R²⁸, and —S(═O)₂NR²⁴R²⁸.

Embodiment 17

The compound of any of Embodiments 1-3, wherein X is chosen fromC₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═)OR²⁸, —C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)NR²⁴R²⁸,—NR²⁴S(═O)₂R²⁸, —OR²⁸, —OC(═O)R²⁸, —S(═O)_(n)R²⁸, and —S(═O)₂NR²⁴R²⁸.

Embodiment 18

The compound of any of Embodiments 1-3, wherein X is chosen fromC₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴S(═O)₂R²⁸, and —OR²⁸.

Embodiment 19

The compound of any of Embodiments 1-3, wherein X is chosen from 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, —C(═O)R²⁸,—C(═O)NR²⁴R²⁸, —NR²⁴R²⁸, —NR²⁴C(═O)R²⁸, —NR²⁴S(═O)₂R²⁸, and —OR²⁸.

Embodiment 20

The compound of any of Embodiments 1-3, wherein X is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹, —NR²⁴R²⁸,and —OR²⁸.

Embodiment 21

The compound of any of Embodiments 1-3, wherein X is chosen from H, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, —NR²⁴R²⁸, and—OR²⁸.

Embodiment 22

The compound of any of Embodiments 1-3, wherein X is chosen fromC₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹, —NR²⁴R²⁸,and —OR²⁸.

Embodiment 23

The compound of any of Embodiments 1-3, wherein X is chosen from 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, —NR²⁴R²⁸, and—OR²⁸.

Embodiment 24

The compound of any of Embodiments 1-3, wherein X is chosen from H, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, and —NR²⁴R²⁸.

Embodiment 25

The compound of any of Embodiments 1-3, wherein X is chosen from 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, and —NR²⁴R²⁸.

Embodiment 26

The compound of any of Embodiments 1-3, wherein X is chosen from H, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, —NR²⁴R²⁸,—OR²⁸, and —SR²⁸.

Embodiment 27

The compound of any of Embodiments 1-3, wherein X is chosen from 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, and—NR²⁴R²⁸.

Embodiment 28

The compound of any of Embodiments 1-3, wherein X is chosen from H, 3-9membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, and—NR²⁴R²⁸.

Embodiment 29

The compound of any of Embodiments 1-3, wherein X is chosen from 3-9membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, and—NR²⁴R²⁸.

Embodiment 30

The compound of any of Embodiments 1-3, wherein X is chosen from H, 3-7membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, and—NR²⁴R²⁸.

Embodiment 31

The compound of any of Embodiments 1-3, wherein X is chosen from 3-7membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, and—NR²⁴R²⁸.

Embodiment 32

The compound of any of Embodiments 1-3, wherein X is 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹.

Embodiment 33

The compound of any of Embodiments 1-3, wherein X is 3-9 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹.

Embodiment 34

The compound of any of Embodiments 1-3, wherein X is 3-7 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹.

Embodiment 35

The compound of any of Embodiments 1-3, wherein X is 5-6 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹.

Embodiment 36

The compound of any of Embodiments 1-3, wherein X is 6 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹.

Embodiment 37

The compound of any of Embodiments 1-3, wherein X is morpholinyl,piperidinyl, or piperazinyl optionally substituted by 1-6 R¹⁹.

Embodiment 38

The compound of any of Embodiments 1-3, wherein X is piperidinyl orpiperazinyl optionally substituted by 1-6 R¹⁹.

Embodiment 39

The compound of any of Embodiments 1-3, wherein X is piperidinyloptionally substituted by 1-6 R¹⁹.

Embodiment 40

The compound of any of Embodiments 1-3, wherein X is piperazinyloptionally substituted by 1-6 R¹⁹.

Embodiment 41

The compound of any of Embodiments 1-3, wherein X is —NR²⁴R²⁸.

Embodiment 42

The compound of any of Embodiments 1-3, wherein X is chosen from H and

wherein

-   -   A is —NR¹R², —CR^(i)R^(j)R^(k), —OR^(18a), or —SR^(18b);    -   Q is —NR¹¹—, —CR^(m)R^(n)—, —O—, or —S—;    -   R^(k) is H, halogen, —CN, —NO₂, —NR¹⁶R¹⁷, —OR^(18c), —SR^(18d),        or —CR^(o)R^(p)R^(q);    -   R^(q) is H, halogen, —CN, —NO₂, —NR^(16a)R^(17a) or —OR^(18e);    -   R¹, R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b),        R^(18c), R^(18d), and R^(18e) are independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R⁷⁹, C₂₋₆alkenyl        optionally substituted by 1-19 R⁷⁹, C₂₋₆alkynyl optionally        substituted by 1-9

R⁷⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁷⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R⁷⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R⁷⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by1-32 R⁷⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28R⁷⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40R⁷⁹, 5-15 membered heteroaryl optionally substituted by 1-15 R⁷⁹, 6-21membered heteroarylalkyl optionally substituted by 1-27 R⁷⁹, and —OR⁷⁰;

-   -   R³, R⁴, R⁵, R⁶, R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁷⁹,        C₂₋₆alkynyl optionally substituted by 1-9 R⁷⁹, C₆₁ aryl        optionally substituted by 1-11 R⁷⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-19 R⁷⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-21 R⁷⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32        R⁷⁹, 3-15 membered heterocycloalkyl optionally substituted by        1-28 R⁷⁹, 4-21 membered heterocycloalkylalkyl optionally        substituted by 1-40 R⁷⁹, 5-15 membered heteroaryl optionally        substituted by 1-15 R⁷⁹, 6-21 membered heteroarylalkyl        optionally substituted by 1-27 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰,        —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —C(═O)C(═O)R⁷⁰, —C(═NR⁷⁵)R⁷⁰,        —C(═NR⁷⁵)NR⁷²R⁷³, —C(═NOH)NR⁷²R⁷³, —C(═NOR⁷⁶)R⁷⁰,        —C(═NNR⁷²R⁷³)R⁷⁰, —C(═NNR⁷⁴C(═O)R⁷¹)R⁷⁰, —C(═NNR⁷⁴C(═O)OR⁷¹)R⁷⁰,        —C(═S)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³, —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴,        —NR⁷⁴OR⁷⁶, —NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)C(═O)R⁷⁰, NR⁷⁴C(═)OR⁷¹,        —NR⁷⁴C(═O)C(═O)OR⁷¹, —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰,        —NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰, —NR⁷⁴C(═NR⁷⁵)NR⁷²R⁷³,        —NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —NR⁷⁴C(═S)R⁷⁰, —NR⁷⁴C(═S)OR⁷⁰,        —NR⁷⁴C(═S)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³,        —NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),        —NR⁷⁴P(═O)(OR⁷⁰)(OR⁷⁰), NR⁷⁴P(═O)(SR⁷⁰)(SR⁷⁰), —OR⁷⁰, —OCN,        —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰, —OC(═NR⁷⁵)NR⁷²R⁷³,        —OS(═O)R⁷⁰, —OS(═O)₂R⁷⁰, —OS(═O)₂OR⁷⁰, —OS(═O)₂NR⁷²R⁷³,        —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —OP(═O)(OR⁷⁰)(OR⁷⁰),        —OP(═O)(SR⁷⁰)(SR⁷⁰), —Si(R⁷⁴)₃, —SCN, —S(═O)_(n)R⁷⁰,        —S(═O)₂OR⁷⁰, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,        —SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),        —SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),        —P(═O)(OR⁷⁰)(OR⁷⁰), and —P(═O)(SR⁷⁰)(SR⁷⁰);        -   or any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹            and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and            R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ and R^(n),            R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and            R¹¹, R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵,            R^(18b) and R^(n), R^(18b) and R^(n), R^(18c) and R^(i), R¹⁸            and R³, R¹⁸ and R⁵, R^(18c) and R¹¹, R^(18c) and R^(n),            R^(18d) and R^(i), R^(18d) and R³, R^(18d) and R⁵, R^(18d)            and R¹¹, and R^(18d) and R^(n) can, together with the atoms            linking them, form a 3-15 membered heterocycloalkyl            optionally substituted by 1-28 R⁷⁹ or a 5-15 membered            heteroaryl optionally substituted by 1-15 R⁷⁹;        -   or any of R³ and R⁴, R³ and R⁶, R⁵ and R⁶, R^(i) and R^(j),            R^(i) and R⁴, R^(i) and R⁵, R^(i) and R¹¹, R^(m) and R^(n),            R⁴ and R^(m), and R⁶ and R^(m) can, together with the atoms            linking them, form a C₆₋₁₁aryl optionally substituted by            1-11 R⁷⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21            R⁷⁹, 3-15 membered heterocycloalkyl optionally substituted            by 1-28 R⁷⁹ or a 5-15 membered heteroaryl optionally            substituted by 1-15 R⁷⁹;        -   or R⁴ and R⁵ or R^(n) and R⁵ can together form a double            bond;        -   or any of R³ and R⁴, R⁵ and R⁶, R^(i) and R^(j), and R^(m)            and R^(n) can together form ═O, ═NR⁷⁰, ═NOR⁷⁰, or ═S.

Embodiment 43

The compound of any of Embodiments 1-3, wherein X is

wherein

-   -   A is —NR¹R², —CR^(i)R^(j)R^(k), —OR^(18a), or —SR^(18b);    -   Q is —NR¹¹—, —CR^(m)R^(n)—, —O—, or —S—;    -   R^(k) is H, halogen, —CN, —NO₂, —NR¹⁶R¹⁷, —OR^(18c), —SR^(18d),        or —CR^(o)R^(p)R^(q);    -   R^(q) is H, halogen, —CN, —NO₂, —NR^(16a)R^(17a) or —OR^(18e)    -   R¹, R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b),        R^(18c), R^(18d), and R^(18e) are independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R⁷⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R⁷⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R⁷⁹, C₆₋₁₁ aryl optionally substituted by        1-11 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁷⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁷⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁷⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁷⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁷⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁷⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R⁷⁹, and —OR⁷⁰;    -   R³, R⁴, R⁵, R⁶, R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-11

R⁷⁹, C₂₋₆alkynyl optionally substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionallysubstituted by 1-11 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R⁷⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁷⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁷⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R⁷⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R⁷⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R⁷⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R⁷⁹, halogen, —CN,—C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —C(═O)C(═O)R⁷⁰, —C(═NR⁷⁵)R⁷⁰,—C(═NR⁷⁵)NR⁷²R⁷³, —C(═NOH)NR⁷²R⁷³, —C(═NOR⁷⁶)R⁷⁰, —C(═NNR⁷²R⁷³)R⁷⁰,—C(═NNR⁷⁴C(═O)R⁷¹)R⁷⁰, —C(═NNR⁷⁴C(═O)OR⁷¹)R⁷⁰, —C(═S)NR⁷²R⁷³, —NC, —NO₂,—NR⁷²R⁷³, —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, —NR⁷⁴OR⁷⁶, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴C(═O)C(═O)R⁷⁰, NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)C(═)OR⁷¹,—NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰,—NR⁷⁴C(═NR⁷⁵)NR⁷²R⁷³, —NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —NR⁷⁴C(═S)R⁷⁰,NR⁷⁴C(═S)OR⁷⁰, —NR⁷⁴C(═S)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³,—NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —NR⁷⁴P(═)(OR⁷⁰)(OR⁷⁰),—NR⁷⁴P(═O)(SR⁷⁰)(SR⁷⁰), —OR⁷⁰, —OCN, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³,—OC(═O)OR⁷⁰, —OC(═NR⁷⁵)NR⁷²R⁷³, —OS(═O)R⁷⁰, —OS(═O)₂R⁷⁰, —OS(═O)₂OR⁷⁰,—OS(═O)₂NR⁷²R⁷³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),—OP(═O)(OR⁷⁰)(OR⁷⁰), —OP(═O)(SR⁷⁰)(SR⁷⁰), —Si(R⁷⁴)₃, —SCN,—S(═O)_(n)R⁷⁰, —S(═O)₂OR⁷⁰, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,—SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),—SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),—P(═O)(OR⁷⁰)(OR⁷⁰), and —P(═O)(SR⁷⁰)(SR⁷⁰);

or any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴and R¹, R⁶ and R¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R⁶ and R³, R¹⁶ and R⁵,R¹⁶ and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) andR⁵, R^(18a) and R¹¹, R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵,R^(18b) and R¹¹, R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³,R^(18c) and R⁵, R^(18C) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i),R^(18d) and R³, R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n)can, together with the atoms linking them, form a 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R⁷⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R⁷⁹;

-   -   or any of R³ and R⁴, R³ and R⁶, R⁵ and R⁶, R^(i) and R^(j),        R^(i) and R⁴, R^(i) and R⁵, R^(i) and R^(n), R^(m) and R^(n), R⁴        and R^(m), and R⁶ and R^(m) can, together with the atoms linking        them, form a C₆₋₁₁aryl optionally substituted by 1-11 R⁷⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁷⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁷⁹ or        a 5-15 membered heteroaryl optionally substituted by 1-15 R⁷⁹;    -   or R⁴ and R⁵ or R^(n) and R⁵ can together form a double bond;    -   or any of R³ and R⁴, R⁵ and R⁶, R^(i) and R^(j), and R^(m) and        R^(n) can together form ═O, ═NR⁷⁰, ═NOR⁷⁰, or ═S.

Embodiment 44

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-10R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionally substituted by1-11 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-10 R⁷⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-10 R⁷⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-10 R⁷⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-10 R⁷⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-10 R⁷⁹, 5-15 membered heteroaryl optionallysubstituted by 1-10 R⁷⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-10 R⁷⁹, and —OR⁷⁰; R³, R⁴, R⁵, R⁶, R^(i), R^(j), R^(m),R^(n), R^(o), and R^(p) are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-10 R⁷⁹, C₂₋₆alkenyl optionally substitutedby 1-10 R⁷⁹, C₂₋₆alkynyl optionally substituted by 1-9 R⁷⁹, C₆₋₁₁aryloptionally substituted by 1-10 R⁷⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-10 R⁷⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-10R⁷⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-10 R⁷⁹, 3-15membered heterocycloalkyl optionally substituted by 1-10 R⁷⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-10 R⁷⁹, 5-15membered heteroaryl optionally substituted by 1-10 R⁷⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-10 R⁷⁹, halogen, —CN,—C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —(═O)C(═O)R⁷⁰, —NC, —NO₂,—NR⁷²R⁷³, —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, —NR⁷⁴OR⁷⁶, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴C(═O)C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)C(═)OR⁷¹,—NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰,—NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³,—NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —NR⁷⁴P(═O)(OR⁷⁰)(OR⁷⁰),—OR⁷⁰, —OCN, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰, —OS(═O)R⁷⁰,—OS(═O)₂R⁷⁰, —OS(═O)₂OR⁷⁰, —OS(═O)₂NR⁷²R⁷³, —OP(═O)R⁷⁸R⁷⁸,—OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —OP(═O)(OR⁷⁰)(OR⁷⁰), —Si(R⁷⁴)₃, —SCN,—S(═O)_(n)R⁷⁰, —S(═O)₂OR⁷⁰, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,—SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),—SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), and—P(═O)(OR⁷⁰)(OR⁷⁰); or any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ andR¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i),R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹,R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹, R^(18a) and R^(n),R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹, R^(18b) and R^(n),R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R¹¹, R^(18e) and R¹¹,R^(18e) and R^(n), R^(18d) and R^(i), R^(18d) and R³, R^(18d) and R⁵,R^(18d) and R¹¹, and R^(18d) and R^(n) can, together with the atomslinking them, form a 3-15 membered heterocycloalkyl optionallysubstituted by 1-10 R⁷⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-10 R⁷⁹; or any of R³ and R⁴, R³ and R⁶, R⁵ and R⁶,R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i) and R^(n), R^(m) andR^(n), R⁴ and R^(m), and R⁶ and R^(m) can, together with the atomslinking them, form a C₆₋₁₁aryl optionally substituted by 1-10 R⁷⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-10 R⁷⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-10 R⁷⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-10 R⁷⁹; or R⁴ and R⁵ or R^(n) andR⁵ can together form a double bond; or any of R³ and R⁴, R⁵ and R⁶,R^(i) and R^(j), and R^(m) and R^(n) can together form ═O, ═NR⁷⁰,═NOR⁷⁰, or ═S.

Embodiment 45

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-10R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionally substituted by1-11 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-10 R⁷⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-10 R⁷⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-10 R⁷⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-10 R⁷⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-10 R⁷⁹, 5-15 membered heteroaryl optionallysubstituted by 1-10 R⁷⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-10 R⁷⁹, and —OR⁷⁰; R³, R⁴, R⁵, R⁶, R^(i), R^(j), R^(m),R^(n), R^(o), and R^(p) are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-10 R⁷⁹, C₂₋₆alkenyl optionally substitutedby 1-10 R⁷⁹, C₂₋₆alkynyl optionally substituted by 1-9 R⁷⁹, C₆₋₁₁aryloptionally substituted by 1-10 R⁷⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-10 R⁷⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-10R⁷⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-10 R⁷⁹, 3-15membered heterocycloalkyl optionally substituted by 1-10 R⁷⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-10 R⁷⁹, 5-15membered heteroaryl optionally substituted by 1-10 R⁷⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-10 R⁷⁹, halogen, —CN,—C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —C(═O)C(═O)R⁷⁰, —NC, —NO₂,—NR⁷²R⁷³, —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, —NR⁷⁴OR⁷⁶, —NR⁷⁴C(═O)R⁷⁰, NR⁷⁴C(═)OR⁷¹,—NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³, —NR⁷⁴P(═O)R⁷⁸R⁷⁸,—NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —NR⁷⁴P(═)(OR⁷⁰)(OR⁷⁰), —OR⁷⁰, —OCN,—OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰, —OS(═O)R⁷⁰, —OS(═O)₂R⁷⁰,—OS(═O)₂OR⁷⁰, —OS(═O)₂NR⁷²R⁷³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),—OP(═O)(OR⁷⁰)(OR⁷⁰), —SCN, —S(═O)_(n)R⁷⁰, —S(═O)₂R⁷⁰, —SO₃R⁷⁷,—S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³, —SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),—SP(═O)(OR⁷⁰)(OR⁷⁰), —SP(═O)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸,—P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), and —P(═O)(OR⁷⁰)(OR⁷⁰); or any of R¹ and R²,R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹,R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³,R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n) can, togetherwith the atoms linking them, form a 3-15 membered heterocycloalkyloptionally substituted by 1-10 R⁷⁹ or a 5-15 membered heteroaryloptionally substituted by 1-10 R⁷⁹; or any of R³ and R⁴, R³ and R⁶, R⁵and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i) and R^(n),R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m) can, together with theatoms linking them, form a C₆₋₁₁aryl optionally substituted by 1-10 R⁷⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-10 R⁷⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-10 R⁷⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-10 R⁷⁹; or R⁴ and R⁵ or R^(n) andR⁵ can together form a double bond; or any of R³ and R⁴, R⁵ and R⁶,R^(i) and R^(j), and R^(m) and R^(n) can together form ═O.

Embodiment 46

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-10R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionally substituted by1-11 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-10 R⁷⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-10 R⁷⁹, C₄₋₁₁cycloalkylalkyloptionally substituted by 1-10 R⁷⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-10 R⁷⁹, 4-11 membered heterocycloalkylalkyloptionally substituted by 1-10 R⁷⁹, 5-11 membered heteroaryl optionallysubstituted by 1-10 R⁷⁹, and 6-12 membered heteroarylalkyl optionallysubstituted by 1-10 R⁷⁹; R³, R⁴, R⁵, R⁶, R^(i), R^(j), R^(m), R^(n),R^(o), and R^(p) are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-10 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-10 R⁷⁹,C₂₋₆alkynyl optionally substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionallysubstituted by 1-10 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-10R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-10 R⁷⁹,C₄₋₁₁cycloalkylalkyl optionally substituted by 1-10 R⁷⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-10 R⁷⁹, 4-11 memberedheterocycloalkylalkyl optionally substituted by 1-10 R⁷⁹, 5-11 memberedheteroaryl optionally substituted by 1-10 R⁷⁹, 6-12 memberedheteroarylalkyl optionally substituted by 1-10 R⁷⁹, halogen, —CN,—C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³, —NR⁷⁴NR⁷²R⁷³,—NR⁷⁴OR⁷⁶, —NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)NR⁷²R⁷³,—NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³, —OR⁷⁰, —OCN, —OC(═O)R⁷⁰,—OC(═O)NR⁷²R⁷³, —OS(═O)R⁷⁰, —OS(═)₂R⁷⁰, —OS(═)₂OR⁷⁰, OS(═)₂NR⁷²R⁷³,—SCN, —S(═O)_(n)R⁷⁰, —S(═O)₂OR⁷⁰, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, and—S(═O)NR⁷²R⁷³; or any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ andR³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹, R^(18a) andR³, R^(18a) and R⁵, R^(18a) and R¹¹, R^(18a) and R^(n), R^(18b) and R³,R^(18b) and R⁵, R^(18b) and R¹¹, R^(18b) and R^(n), R^(18c) and R^(i),R^(18C) and R³, R^(18c) and R⁵, R^(18c) and R¹¹,R^(18c) and R^(n),R^(18d) and R^(i), R^(18d) and R³, R^(18d) and R⁵, R^(18d) and R¹¹, andR^(18d) and R^(n) can, together with the atoms linking them, form a 3-11membered heterocycloalkyl optionally substituted by 1-10 R⁷⁹ or a 5-11membered heteroaryl optionally substituted by 1-10 R⁷⁹; or any of R³ andR⁴, R³ and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵,R^(i) and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m) can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-10 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-10R⁷⁹, 3-11 membered heterocycloalkyl optionally substituted by 1-10 R⁷⁹or a 5-11 membered heteroaryl optionally substituted by 1-10 R⁷⁹; or R⁴and R⁵ or R^(n) and R⁵ can together form a double bond; or any of R³ andR⁴, R⁵ and R⁶, R^(i) and R^(j), and R^(m) and R^(n) can together form═O.

Embodiment 47

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹,

R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), andR^(18e) are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-10 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁷⁹,C₂₋₆alkynyl optionally substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionallysubstituted by 1-11 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-10R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-10 R⁷⁹,C₄₋₁₁cycloalkylalkyl optionally substituted by 1-10 R⁷⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-10 R⁷⁹, 4-11 memberedheterocycloalkylalkyl optionally substituted by 1-10 R⁷⁹, 5-11 memberedheteroaryl optionally substituted by 1-10 R⁷⁹, and 6-12 memberedheteroarylalkyl optionally substituted by 1-10 R⁷⁹; R³, R⁴, R⁵, R⁶,R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are independently chosenfrom H, C₁₋₆alkyl optionally substituted by 1-10 R⁷⁹, C₂₋₆alkenyloptionally substituted by 1-10 R⁷⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R⁷⁹, C₆₋₁₁aryl optionally substituted by 1-10 R⁷⁹, C₇₋₁₆arylalkyloptionally substituted by 1-10 R⁷⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-10 R⁷⁹, C₄₋₁₁cycloalkylalkyl optionally substituted by1-10 R⁷⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-10R⁷⁹, 4-11 membered heterocycloalkylalkyl optionally substituted by 1-10R⁷⁹, 5-11 membered heteroaryl optionally substituted by 1-10 R⁷⁹, 6-12membered heteroarylalkyl optionally substituted by 1-10 R⁷⁹, halogen,—CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³,—NR⁷⁴OR⁷⁶, —NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)NR⁷²R⁷³,—NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³, —OR⁷⁰, —OCN, —OC(═O)R⁷⁰,—OC(═O)NR⁷²R⁷³, —SCN, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³; or any of R¹and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ andR¹¹, R¹⁶ and R^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵,R^(18a) and R¹¹, R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵,R^(18b) and R¹¹, R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³,R^(18c) and R⁵, R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i),R^(18d) and R³, R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n)can, together with the atoms linking them, form a 3-11 memberedheterocycloalkyl optionally substituted by 1-10 R⁷⁹ or a 5-11 memberedheteroaryl optionally substituted by 1-10 R⁷⁹; or any of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i)and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m) can, togetherwith the atoms linking them, form a C₆₋₁₁aryl optionally substituted by1-10 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-10 R⁷⁹, 3-11membered heterocycloalkyl optionally substituted by 1-10 R⁷⁹ or a 5-11membered heteroaryl optionally substituted by 1-10 R⁷⁹; or R⁴ and R⁵ orR^(n) and R⁵ can together form a double bond; or any of R³ and R⁴, R⁵and R⁶, R^(i) and R^(j), and R^(m) and R^(n) can together form ═O.

Embodiment 48

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-10R⁷⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁷⁹, C₇₋₁₆arylalkyloptionally substituted by 1-10 R⁷⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-10 R⁷⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-10 R⁷⁹, and 5-11 membered heteroaryl optionallysubstituted by 1-10 R⁷⁹; R³, R⁴, R⁵, R⁶, R^(i), R^(j), R^(m), R^(n),R^(o), and R^(p) are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-10 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-10 R⁷⁹,C₂₋₆alkynyl optionally substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionallysubstituted by 1-10 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-10R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-10 R⁷⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-10 R⁷⁹, 5-11 memberedheteroaryl optionally substituted by 1-10 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰,—C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³, —NR⁷⁴OR⁷⁶,—NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹,—NR⁷⁴S(═O)₂NRR⁷²R⁷³, —OR⁷⁰, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —S(═O)_(n)R⁷⁰,and —S(═O)₂NR⁷²R⁷³; or any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ andR¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i),R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹,R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹, R^(18a) and R^(n),R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹, R^(18b) and R^(n),R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵, R^(18c) and R¹¹,R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³, R^(18d) and R⁵,R^(18d) and R¹¹, and R^(18d) and R^(n) can, together with the atomslinking them, form a 3-11 membered heterocycloalkyl optionallysubstituted by 1-10 R⁷⁹ or a 5-11 membered heteroaryl optionallysubstituted by 1-10 R⁷⁹; or any of R³ and R⁴, R³ and R⁶, R⁵ and R⁶,R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i) and R^(n), R^(m) andR^(n), R⁴ and R^(m), and R⁶ and R^(m) can, together with the atomslinking them, form a C₆₋₁₁aryl optionally substituted by 1-10 R⁷⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-10 R⁷⁹, 3-11 memberedheterocycloalkyl optionally substituted by 1-10 R⁷⁹ or a 5-11 memberedheteroaryl optionally substituted by 1-10 R⁷⁹; or R⁴ and R⁵ or R^(n) andR⁵ can together form a double bond; or any of R³ and R⁴, R⁵ and R⁶,R^(i) and R^(j), and R^(m) and R^(n) can together form ═O.

Embodiment 49

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R⁷⁹, C₆₋₁₁aryl optionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyloptionally substituted by 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-6 R⁷⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R⁷⁹, and 5-11 membered heteroaryl optionallysubstituted by 1-6 R⁷⁹; R³, R⁴, R⁵, R⁶, R^(i), R^(j), R^(m), R^(n),R^(o), and R^(p) are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-6 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-6 R⁷⁹,C₂₋₆alkynyl optionally substituted by 1-6 R⁷⁹, C₆₋₁₁aryl optionallysubstituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R⁷⁹, 5-11 memberedheteroaryl optionally substituted by 1-6 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰,—C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³, —NR⁷⁴OR⁷⁶,—NR⁷⁴C(═O)R⁷⁰, NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹,—NR⁷⁴S(═O)₂NR⁷²R⁷²R, —OR⁷⁰, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —S(═O)_(n)R⁷⁰,and —S(═O)₂NR⁷²R⁷³; or any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ andR¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i),R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹,R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹, R^(18a) and R^(n),R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹, R^(18b) and R^(n), andR^(i), R^(18c) and R³, R^(18c) and R⁵, R^(18c) and R¹¹, R^(18c) andR^(n), R^(18d) and R^(i), R^(18d) and R³, R^(18d) and R⁵, R^(18d) andR¹¹, and R^(18d) and R^(n) can, together with the atoms linking them,form a 3-11 membered heterocycloalkyl optionally substituted by 1-6 R⁷⁹or a 5-11 membered heteroaryl optionally substituted by 1-6 R⁷⁹; or anyof R³ and R⁴, R³ and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i)and R⁵, R^(i) and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m)can, together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6R⁷⁹, 3-11 membered heterocycloalkyl optionally substituted by 1-6 R⁷⁹ ora 5-11 membered heteroaryl optionally substituted by 1-6 R⁷⁹; or R⁴ andR⁵ or R^(n) and R⁵ can together form a double bond; or any of R³ and R⁴,R⁵ and R⁶, R^(i) and R^(j), and R^(m) and R^(n) can together form ═O.

Embodiment 50

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R⁷⁹, and C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹; R³, R⁴, R⁵,R⁶, R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R⁷⁹, halogen,—CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³,—NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰, —S(═O)_(n)R⁷⁰, and—S(═O)₂NR⁷²R⁷³2R; or any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹,R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹, R^(18a)and R³, R^(18a) and R⁵, R^(18a) and R¹¹, R^(18a) and R^(n), R^(18b) andR³, R^(18b) and R⁵, R^(18b) and R¹¹, R^(18b) and R^(n), R^(18c) andR^(i), R^(18c) and R³, R^(18c) and R⁵, R^(18c) and R¹¹, R^(18c) andR^(n), R^(18d) and R^(i), R^(18d) and R³, R^(18d) and R⁵, R^(18d) andR¹¹, and R^(18d) and R^(n) can, together with the atoms linking them,form a 3-11 membered heterocycloalkyl optionally substituted by 1-6 R⁷⁹;or any of R³ and R⁴, R³ and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) andR⁴, R^(i) and R⁵, R^(i) and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶and R^(m) can, together with the atoms linking them, form aC₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, or a 3-11 memberedheterocycloalkyl optionally substituted by 1-6 R⁷⁹; or any of R³ and R⁴,R⁵ and R⁶, R^(i) and R^(j), and R^(m) and R^(n) can together form ═O.

Embodiment 51

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R⁷⁹, and C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹; R³, R⁴, R⁵,R⁶, R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-6membered heterocycloalkyl optionally substituted by 1-6 R⁷⁹, halogen,—CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³; orany of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ andR¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵,R^(18a) and R¹¹, R^(18a) and R^(n), R^(18c) and R^(i), R^(18c) and R³,R^(18c) and R⁵, R^(18c) and R¹¹, and R^(18c) and R^(n) can, togetherwith the atoms linking them, form a 3-11 membered heterocycloalkyloptionally substituted by 1-6 R⁷⁹; or any of R³ and R⁴, R³ and R⁶, R⁵and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i) and R^(n),R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m) can, together with theatoms linking them, form a C₃₋₁₀cycloalkyl optionally substituted by 1-6R⁷⁹, or a 3-11 membered heterocycloalkyl optionally substituted by 1-6R⁷⁹; or any of R³ and R⁴, R⁵ and R⁶, R^(i) and R^(j), and R^(m) andR^(n) can together form ═O.

Embodiment 52

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R⁷⁹, and C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹; R³, R⁴, R⁵,R⁶, R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-6membered heterocycloalkyl optionally substituted by 1-3 R⁷⁹, halogen,—CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³; orany of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ andR¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵,R^(18a) and R¹¹, R^(18a) and R^(n), R^(18c) and R^(i), R^(18c) and R³,R^(18c) and R⁵, R^(18c) and R¹¹, and R^(18c) and R^(n) can, togetherwith the atoms linking them, form a 3-11 membered heterocycloalkyloptionally substituted by 1-6 R⁷⁹; or any of R³ and R⁴, R⁵ and R⁶, R^(i)and R^(l), and R^(m) and R^(n) can together form ═O.

Embodiment 53

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R⁷⁹, and C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹; R³, R⁴, R⁵,R⁶, R^(i), R^(l), R^(m), R^(n), R^(o), and R^(p) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-6membered heterocycloalkyl optionally substituted by 1-3 R⁷⁹, halogen,—CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³2R;or any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴and R¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵,R¹⁶ and R¹, R¹⁶ and R^(n), R^(j) and R¹¹, and R^(18a) and R¹¹ can,together with the atoms linking them, form a 3-11 memberedheterocycloalkyl optionally substituted by 1-6 R⁷⁹; or any of R³ and R⁴,R⁵ and R⁶, R^(i) and R^(j), and R^(m) and R^(n) can together form ═O.

Embodiment 54

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R⁷⁹, and C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹; R³, R⁴, R⁵,R⁶, R^(i), R^(l), R^(m), R^(n), R^(o), and R^(p) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, halogen,—CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰, —S(═)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³2R;or any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴and R¹¹, R¹⁶ and R⁵, R^(j) and R¹¹, and R^(18a) and R¹¹ can, togetherwith the atoms linking them, form a 3-11 membered heterocycloalkyloptionally substituted by 1-6 R⁷⁹; or R³ and R⁴ can together form ═O.

Embodiment 55

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R⁷⁹, and C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹; R³, R⁴, R⁵,R⁶, R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are independentlychosen from H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, —CN,—C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, and —OR⁷⁰; or any of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R¹⁶ and R⁵,R^(j) and R¹¹, and R^(18a) and R¹¹ can, together with the atoms linkingthem, form a 3-11 membered heterocycloalkyl optionally substituted by1-6 R⁷⁹; or R³ and R⁴ can together form ═O.

Embodiment 56

The compound of Embodiments 42 or 43, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b),R^(18c), R^(18d), and R^(18e) areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-6R⁷⁹; R⁴, R⁵, R⁶, R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R⁷⁹, and C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹; R³ is chosenfrom H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyloptionally substituted by 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-6 R⁷⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰, C(═O)OR⁷⁰,—C(═O)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³, —NR⁷⁴OR⁷⁶, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³,—OR⁷⁰, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³; orany of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ andR¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶and R^(18d), R¹⁶ and R^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) andR⁵, R^(18a) and R¹¹, R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵,R^(18b) and R¹¹, R^(18b) and R^(n), R^(18c) and R^(i), R^(18e) and R³,R^(18c) and R⁵, R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i),R^(18d) and R³, R^(18d) and R⁵, R^(18d) and R¹, and R^(18d) and R^(n)can, together with the atoms linking them, form a 3-11 memberedheterocycloalkyl optionally substituted by 1-6 R⁷⁹ or a 5-11 memberedheteroaryl optionally substituted by 1-6 R⁷⁹; or any of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i)and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m) can, togetherwith the atoms linking them, form a C₆₋₁₁aryl optionally substituted by1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-11membered heterocycloalkyl optionally substituted by 1-6 R⁷⁹ or a 5-11membered heteroaryl optionally substituted by 1-6 R⁷⁹; or R⁴ and R⁵ orR^(n) and R⁵ can together form a double bond; or any of R³ and R⁴, R⁵and R⁶, R^(i) and R^(j), and R^(m) and R^(n) can together form ═O.

Embodiment 57

The compound of Embodiments 42 or 43, wherein R¹, R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-6R⁷⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹,and C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹; R⁴, R⁵, R⁶, R^(i),R^(j), R^(m), R^(n), R^(o), and R^(p) are independently chosen from Hand C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyl optionallysubstituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R⁷⁹, halogen, —CN,—C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³; orany of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ andR¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵,R^(18a) and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵,R^(18b) and R¹¹, R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³,R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n) can, togetherwith the atoms linking them, form a 3-11 membered heterocycloalkyloptionally substituted by 1-6 R⁷⁹; or any of R³ and R⁴, R³ and R⁶, R⁵and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i) and R^(n),R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m) can, together with theatoms linking them, form a C₃₋₁₀cycloalkyl optionally substituted by 1-6R⁷⁹, or a 3-11 membered heterocycloalkyl optionally substituted by 1-6R⁷⁹; or any of R³ and R⁴, R⁵ and R⁶, R^(i) and R^(j), and R^(m) andR^(n) can together form ═O.

Embodiment 58

The compound of Embodiments 42 or 43, wherein R¹, R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-6R⁷⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹,and C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹; R⁴, R⁵, R⁶, R^(i),R^(j), R^(m), R^(n), R^(o), and R^(p) are independently chosen from Hand C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyl optionallysubstituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-6 R⁷⁹, halogen, —CN,—C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³; orany of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ andR¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵,R^(18a) and R¹¹, R^(18a) and R^(n), R^(18c) and R^(i), R^(18c) and R³,R^(18c) and R⁵, R^(18c) and R¹¹, and R^(18c) and R^(n) can, togetherwith the atoms linking them, form a 3-11 membered heterocycloalkyloptionally substituted by 1-6 R⁷⁹; or any of R³ and R⁴, R³ and R⁶, R⁵and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i) and R^(n),R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m) can, together with theatoms linking them, form a C₃₋₁₀-cycloalkyl optionally substituted by1-6 R⁷⁹, or a 3-11 membered heterocycloalkyl optionally substituted by1-6 R⁷⁹; or any of R³ and R⁴, R⁵ and R⁶, R^(i) and R^(j), and R^(m) andR^(n) can together form ═O.

Embodiment 59

The compound of Embodiments 42 or 43, wherein R¹, R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) areindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-6R⁷⁹; R² is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹,and C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹; R⁴, R⁵, R⁶, R^(i),R^(j), R^(m), R^(n), R^(o), and R^(p) are independently chosen from Hand C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹; R³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyl optionallysubstituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁷⁹, halogen, —CN,—C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³; orany of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ andR¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵,R^(18a) and R¹¹, R^(18a) and R^(n), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, and R^(18c) and R^(n) can, together with the atomslinking them, form a 3-11 membered heterocycloalkyl optionallysubstituted by 1-6 R⁷⁹; or any of R³ and R⁴, R⁵ and R⁶, R^(i) and R^(j),and R^(m) and R^(n) can together form ═O.

Embodiment 60

The compound of any of Embodiments 42-59, wherein 0-3 of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³,R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n), together withthe atoms linking them, form an optionally substituted heterocycloalkylor an optionally substituted heteroaryl.

Embodiment 61

The compound of any of Embodiments 42-59, wherein 0-2 of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R³, R^(18a) and R⁵,R^(18a) and R¹¹, R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵,R^(18b) and R¹¹, R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³,R^(18c) and R⁵, R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i),R^(18d) and R³, R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n),together with the atoms linking them, form an optionally substitutedheterocycloalkyl or an optionally substituted heteroaryl.

Embodiment 62

The compound of any of Embodiments 42-59, wherein 1-2 of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³,R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n), together withthe atoms linking them, form an optionally substituted heterocycloalkylor an optionally substituted heteroaryl.

Embodiment 63

The compound of any of Embodiments 42-59, wherein none of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) andR^(i), R^(18d) and R³, R^(18d) and R, R^(18d) and R¹¹, and R^(18d) andR^(n), together with the atoms linking them, form an optionallysubstituted heterocycloalkyl or an optionally substituted heteroaryl.

Embodiment 64

The compound of any of Embodiments 42-59, wherein one of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³,R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n), together withthe atoms linking them, form an optionally substituted heterocycloalkylor an optionally substituted heteroaryl.

Embodiment 65

The compound of any of Embodiments 42-59, wherein two of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n),R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³,R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n), together withthe atoms linking them, form an optionally substituted heterocycloalkylor an optionally substituted heteroaryl.

Embodiment 66

The compound of any of Embodiments 42-59, wherein 0-3 of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³,R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n), together withthe atoms linking them, form an optionally substituted heterocycloalkyl.

Embodiment 67

The compound of any of Embodiments 42-59, wherein 0-2 of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³,R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n), together withthe atoms linking them, form an optionally substituted heterocycloalkyl.

Embodiment 68

The compound of any of Embodiments 42-59, wherein 1-2 of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³,R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) R^(n), together with theatoms linking them, form an optionally substituted heterocycloalkyl.

Embodiment 69

The compound of any of Embodiments 42-59, wherein none of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³,R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n), together withthe atoms linking them, form an optionally substituted heterocycloalkyl.

Embodiment 70

The compound of any of Embodiments 42-59, wherein one of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R¹⁸, R^(i), R^(18d) and R³, R^(18d)and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n), together with the atomslinking them, form an optionally substituted heterocycloalkyl.

Embodiment 71

The compound of Embodiment 70, wherein said optionally substitutedheterocarbocyclyl is a 3-7 membered heterocarbocycl optionallysubstituted with 1-4 R⁷⁹.

Embodiment 72

The compound of Embodiment 70, wherein said optionally

substituted heterocarbocyclyl is a 5-6 membered heterocarbocycloptionally substituted with 1-4 R⁷⁹.

Embodiment 73

The compound of any of Embodiments 42-59, wherein two of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ andR^(n), R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R¹⁸ and R¹¹,R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d) and R³,R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n), together withthe atoms linking them, form an optionally substituted heterocycloalkyl.

Embodiment 74

The compound of any of Embodiments 42-73, wherein 0-2 of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i)and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), togetherwith the atoms linking them, form an optionally substutituted aryl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, or optionally substituted heteroaryl.

Embodiment 75

The compound of any of Embodiments 42-73, wherein 0-1 of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R, R^(i) and R⁴, R^(i) and R⁵, R¹ andR^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), together withthe atoms linking them, form an optionally substutituted aryl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, or optionally substituted heteroaryl.

Embodiment 76

The compound of any of Embodiments 42-73, wherein none of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R¹ and R, R^(i) and R⁴, R^(i) and R⁵, R^(i) andR^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), together withthe atoms linking them, form an optionally substutituted aryl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, or optionally substituted heteroaryl.

Embodiment 77

The compound of any of Embodiments 42-73, wherein one of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i)and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), togetherwith the atoms linking them, form an optionally substutituted aryl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, or optionally substituted heteroaryl.

Embodiment 78

The compound of any of Embodiments 42-73, wherein 0-2 of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i)and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), togetherwith the atoms linking them, form an optionally substutituted cycloalkylor optionally substituted heterocycloalkyl.

Embodiment 79

The compound of any of Embodiments 42-73, wherein 0-1 of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i)and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), togetherwith the atoms linking them, form an optionally substutituted cycloalkylor optionally substituted heterocycloalkyl.

Embodiment 80

The compound of any of Embodiments 42-73, wherein none of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i)and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), togetherwith the atoms linking them, form an optionally substutituted cycloalkylor optionally substituted heterocycloalkyl.

Embodiment 81

The compound of any of Embodiments 42-73, wherein one of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i)and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), togetherwith the atoms linking them, form an optionally substutituted cycloalkylor optionally substituted heterocycloalkyl.

Embodiment 82

The compound of any of Embodiments 42-73, wherein 0-2 of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R¹ and R, R^(i) and R⁴, R^(i) and R⁵, R^(i) andR^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), together withthe atoms linking them, form an optionally substutitutedheterocycloalkyl.

Embodiment 83

The compound of any of Embodiments 42-73, wherein 0-1 of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i)and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), togetherwith the atoms linking them, form an optionally substutitutedheterocycloalkyl.

Embodiment 84

The compound of any of Embodiments 42-73, wherein none of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i)and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), togetherwith the atoms linking them, form an optionally substutitutedheterocycloalkyl.

Embodiment 85

The compound of any of Embodiments 42-73, wherein one of R³ and R⁴, R³and R⁶, R⁵ and R⁶, R^(i) and R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i)and R^(n), R^(m) and R^(n), R⁴ and R^(m), and R⁶ and R^(m), togetherwith the atoms linking them, form an optionally substutitutedheterocycloalkyl.

Embodiment 86

The compound of Embodiment 85, wherein said optionally substitutedheterocarbocyclyl is a 3-7 membered heterocarbocycl optionallysubstituted with 1-4 R⁷⁹.

Embodiment 87

The compound of Embodiment 85, wherein said optionally substitutedheterocarbocyclyl is a 5-6 membered heterocarbocycl optionallysubstituted with 1-4 R⁷⁹.

Embodiment 88

The compound of any of Embodiments 42-87, wherein neither R⁴ and R⁵ norR^(n) and R⁵ together form a double bond.

Embodiment 89

The compound of any of Embodiments 42-88, wherein none of R³ and R⁴, R⁵and R⁶, R^(i) and R^(j), or R^(m) and R^(n) together form ═O, ═NR⁷⁰,═NOR⁷⁰, or ═S.

Embodiment 90

The compound of Embodiments 42 or 43, wherein R¹, R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) are H;R² is chosen from H and C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹; R⁴,R⁵, R⁶, R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are H; R³ is chosenfrom H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-6membered heterocycloalkyl optionally substituted by 1-3 R⁷⁹, halogen,—CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰,NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰, —S(═)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³; orany of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ andR¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹, and R^(18a) and R¹¹ can, togetherwith the atoms linking them, form a 3-11 membered heterocycloalkyloptionally substituted by 1-6 R⁷⁹; or any of R³ and R⁴, R⁵ and R⁶, R^(i)and R^(j), and R^(m) and R^(n) can together form ═O.

Embodiment 91

The compound of Embodiments 42 or 43, wherein R¹, R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) are H;R² is chosen from H and C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹; R⁴,R⁵, R⁶, R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are H; R³ is chosenfrom H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, halogen,—CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, OC(═O)R⁷⁰, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷²R; orany of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ andR¹, R¹⁶ and R⁵, R^(l) and R¹, and R^(18a) and R¹¹ can, together with theatoms linking them, form a 3-11 membered heterocycloalkyl optionallysubstituted by 1-6 R⁷⁹; or R³ and R⁴ can together form ═O.

Embodiment 92

The compound of Embodiments 42 or 43, wherein R¹, R¹, R¹⁶, R¹⁷, R^(16a),R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) are H; R² ischosen from H and C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹; R⁴, R⁵,R⁶, R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are H; R³ is chosenfrom H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyloptionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, —CN,—C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, and —OR⁷⁰; or any of R¹ and R², R¹and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹, R¹⁶ and R⁵,R^(j) and R¹¹, and R^(18a) and R¹¹ can, together with the atoms linkingthem, form a 3-11 membered heterocycloalkyl optionally substituted by1-6 R⁷⁹; or R³ and R⁴ can together form ═O.

Embodiment 93

The compound of any of Embodiments 42-89, wherein at least five of R¹,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d),and R^(18e) are H; and at least four of R³, R⁴, R⁵, R⁶, R^(i), R^(j),R^(m), R^(n), R^(o), and R^(p) are H.

Embodiment 94

The compound of any of Embodiments 42-89, wherein at least five of R¹,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d),and R^(18e) are H; and at least five of R³, R⁴, R⁵, R⁶, R^(i), R^(j),R^(m), R^(n), R^(o), and R^(p) are H.

Embodiment 95

The compound of any of Embodiments 42-89, wherein at least six of R¹,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d),and R^(18e) are H; and at least five of R³, R⁴, R⁵, R⁶, R^(i), R^(j),R^(m), R^(n), R^(o), and R^(p) are H.

Embodiment 96

The compound of any of Embodiments 42-89, wherein at least six of R¹,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d),and R^(18e) are H; and at least six of R³, R⁴, R⁵, R⁶, R^(i), R^(j),R^(m), R^(n), R^(o), and R^(p) are H.

Embodiment 97

The compound of any of Embodiments 42-89, wherein at least seven of R¹,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d),and R^(18e) are H; and at least six of R³, R⁴, R⁵, R⁶, R^(i), R^(j),R^(m), R^(n), R^(o), and R^(p) are H.

Embodiment 98

The compound of any of Embodiments 42-89, wherein at least seven of R¹,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d),and R^(18e) are H; and at least seven of R³, R⁴, R⁵, R⁶, R^(i), R^(j),R^(m), R^(n), R^(o), and R^(p) are H.

Embodiment 99

The compound of any of Embodiments 42-89, wherein at least eight of R¹,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d),and R^(18e) are H; and at least seven of R³, R⁴, R⁵, R⁶, R^(i), R^(j),R^(m), R^(n), R^(o), and R^(p) are H.

Embodiment 100

The compound of any of Embodiments 42-89, wherein at least eight of R¹,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d),and R^(18e) are H; and at least eight of R³, R⁴, R⁵, R⁶, R^(i), R^(j),R^(m), R^(n), R^(o), and R^(p) are H.

Embodiment 101

The compound of any of Embodiments 42-89, wherein at least nine of R,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R¹⁸, R^(18d), andR^(18e) are H; and at least eight of R³, R⁴, R⁵, R⁶, R^(i), R^(j),R^(m), R^(n), R^(o), and R^(p) are H.

Embodiment 102

The compound of any of Embodiments 42-89, wherein at least nine of R,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R¹⁸, R^(18d), andR^(18e) are H; and at least nine of R³, R⁴, R⁵, R⁶, R^(i), R^(j), R^(m),R^(n), R^(o), and R^(p) are H.

Embodiment 103

The compound of any of Embodiments 42-89, wherein at least ten of R¹,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d),and R^(e) are H; and at least nine of R³, R⁴, R⁵, R⁶, R^(i),R^(j),R^(m), R^(n), R^(o), and R^(p) are H.

Embodiment 104

The compound of any of Embodiments 42-89, wherein at least eleven of R¹,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d),and R^(18e) are H; and at least nine of R³, R⁴, R⁵, R⁶, R^(i), R^(j),R^(m), R^(n), R^(o), and R^(p) are H.

Embodiment 105

The compound of any of Embodiments 42-89, wherein R¹, R², R¹¹, R¹⁶, R¹⁷,R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d), and R^(18e) are H;and at least nine of R³, R⁴, R⁵, R⁶, R^(i) R^(j), R^(m), R^(n), R^(o),and R^(p) are H.

Embodiment 106

The compound of any of Embodiments 42-89, wherein at least eleven of R¹,R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c), R^(18d),and R^(18e) are H; and R³, R⁴, R⁵, R⁶, R^(i), R^(j), R^(m), R^(n),R^(o), and R^(p) are H.

Embodiment 107

The compound of any of Embodiments 42-106, wherein R^(q) is H,—NR^(16a)R^(7a) or —OR^(18e).

Embodiment 108

The compound of any of Embodiments 42-106, wherein R^(q) is—NR^(16a)R^(7a) or —OR^(18e).

Embodiment 109

The compound of any of Embodiments 42-108, wherein R^(k) is H, halogen,—CN, —NR¹⁶R¹⁷, —OR¹⁸, —SR^(18d), or —CR^(o)R^(p)R^(q).

Embodiment 110

The compound of any of Embodiments 42-108, wherein R^(k) is H, —CN,—NR¹⁶R¹⁷, —OR^(18c), —SR^(18d), or —CR^(o)R^(p)R^(q).

Embodiment 111

The compound of any of Embodiments 42-108, wherein R^(k) is H, —CN,—NR¹⁶R¹⁷, —OR^(18c), or —CR^(o)R^(p)R^(q).

Embodiment 112

The compound of any of Embodiments 42-108, wherein R^(k) is H, —NR¹⁶R¹⁷,—OR^(18c), or —CR^(o)R^(p)R^(q).

Embodiment 113

The compound of any of Embodiments 42-108, wherein R^(k) is —NR¹⁶R¹⁷,—OR^(18c), or —CR^(o)R^(p)R^(q).

Embodiment 114

The compound of any of Embodiments 42-106, wherein R^(k) is H.

Embodiment 115

The compound of any of Embodiments 42-106, wherein R^(k) is —NR¹⁶R¹⁷.

Embodiment 116

The compound of any of Embodiments 42-106, wherein R^(k) is —OR¹⁸c.

Embodiment 117

The compound of any of Embodiments 42-108, wherein R^(k) is—CR^(o)R^(p)R^(q).

Embodiment 118

The compound of any of Embodiments 42-117, wherein A is —NR¹R²,—CR^(i)R^(j)R^(k), or —OR^(18a).

Embodiment 119

The compound of any of Embodiments 42-106, wherein A is —NR¹R² or—OR^(18a).

Embodiment 120

The compound of any of Embodiments 42-117, wherein A is—CR^(i)R^(j)R^(k).

Embodiment 121

The compound of any of Embodiments 42-106, wherein A is —NR¹R².

Embodiment 122

The compound of any of Embodiments 42-106, wherein A is —OR^(18a).

Embodiment 123

The compound of any of Embodiments 42-122, wherein Q is —NR¹¹—,—CR^(m)R^(n)—, or —O—.

Embodiment 124

The compound of any of Embodiments 42-122, wherein Q is —NR¹¹—.

Embodiment 125

The compound of any of Embodiments 42-122, wherein Q is —CR^(m)R^(n)—.

Embodiment 126

The compound of any of Embodiments 42-122, wherein Q is —O—.

Embodiment 127

The compound of any of Embodiments 42-106, wherein A is —NR¹R²,—CR^(i)R^(j)R^(k), or —OR^(18a); Q is —NR¹¹—, —CR^(m)R^(n)—, or —O—; andR^(k) is —NR¹⁶R¹⁷, or —OR^(18c).

Embodiment 128

The compound of any of Embodiments 42-106, wherein A is —NR¹R²,—CR^(i)R^(j)R^(k), or —OR^(18a); Q is —NR¹¹—; and R^(k) is —NR¹⁶R¹⁷, or—OR^(18c).

Embodiment 129

The compound of any of Embodiments 42-106, wherein A is —NR¹R²,—CR^(i)R^(j)R^(k), or —OR^(18a); Q is —NR¹¹—; and R^(k) is —OR^(18c).

Embodiment 130

The compound of any of Embodiments 42-106, wherein A is —NR¹R² or—OR^(18a); and Q is —NR¹¹—.

Embodiment 131

The compound of any of Embodiments 42-106, wherein A is —NR¹R²; and Q is—NR¹¹—.

Embodiment 132

The compound of any of Embodiments 1-3, wherein X is chosen from —NHR²⁸and 3-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2nitrogen atoms in which the heterocycloalkyl is optionally substitutedby 1-6 R¹⁹.

Embodiment 133

The compound of any of Embodiments 1-3, wherein X is chosen from —NHR²⁸and 5-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2nitrogen atoms in which the heterocycloalkyl is optionally substitutedby 1-6 R¹⁹.

Embodiment 134

The compound of any of Embodiments 1-3, wherein X is chosen from —NHR²⁸and 5-9 membered heterocycloalkyl consisting of carbon atoms and 1 or 2nitrogen atoms in which the heterocycloalkyl is optionally substitutedby 1-6 R¹⁹.

Embodiment 135

The compound of any of Embodiments 1-3, wherein X is chosen from —NHR²⁸and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2nitrogen atoms in which the heterocycloalkyl is optionally substitutedby 1-6 R¹⁹.

Embodiment 136

The compound of any of Embodiments 1-3, wherein X is chosen

from —NHR²⁸ and 5-10 membered heterocycloalkyl consisting of carbonatoms and 1 or 2 nitrogen atoms in which the heterocycloalkyl isoptionally substituted by 1 or 2 members chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl optionally substituted by1-3 R³⁹, C₆₋₁₁aryl optionally substituted by 1-3 R³⁹, C₇₋₁₆arylalkyloptionally substituted by 1-3 R³⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-3 R³⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-3 R³⁹, halogen, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³,—NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰.

Embodiment 137

The compound of any of Embodiments 1-3, wherein X is chosen from —NHR²⁸and 5-10 membered heterocycloalkyl consisting of carbon atoms and 1 or 2nitrogen atoms in which the heterocycloalkyl is optionally substitutedby 1 or 2 members chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₂₋₆alkynyl, C₆₋₁₁aryl, C₇₋₁₆arylalkyl optionally substituted by1-3 R³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R³⁹, 5-10membered heterocycloalkyl, halogen, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³,—NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰.

Embodiment 138

The compound of any of Embodiments 1-3, wherein X is chosen from —NHR²⁸and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2nitrogen atoms in which the heterocycloalkyl is optionally substitutedby 1 or 2 members chosen from C₁₋₆alkyl optionally substituted by 1-3R³⁹, C₂₋₆alkynyl, C₆₋₁₁aryl, C₇₋₁₆arylalkyl optionally substituted by1-3 R³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R³⁹, 5-10membered heterocycloalkyl, halogen, —CN, —C(═)OR³⁰, —C(═O)NR³²R³³,—NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰.

Embodiment 139

The compound of any of Embodiments 1-3, wherein X is chosen from —NHR²⁸and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2nitrogen atoms in which the heterocycloalkyl is optionally substitutedby 1 or 2 members chosen from C₁₋₆alkyl optionally substituted by 1-6halogen, halogen, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³,—NR³⁴C(═O)R³⁰, and —OR³⁰.

Embodiment 140

The compound of any of Embodiments 1-3, wherein X is chosen from —NHR²⁸and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2nitrogen atoms in which the heterocycloalkyl is optionally substitutedby 1 or 2 members chosen from C₁₋₆alkyl optionally substituted by 1-6halogen, halogen, —CN, and —OH.

Embodiment 141

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(C₇₋₁₁arylalkyloptionally substituted by 1-6 R⁴⁹), —NH(3-10 membered heterocycloalkyloptionally substituted by 1-6 R⁴⁹), —NH(4-11 memberedheterocycloalkylalkyl optionally substituted by 1-6 R⁴⁹), and 3-10membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogenatoms in which the heterocycloalkyl is optionally substituted by 1-6R¹⁹.

Embodiment 142

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(C₇₋₁₁arylalkyloptionally substituted by 1-6 R⁴⁹), —NH(3-10 membered heterocycloalkyl),—NH(4-11 membered heterocycloalkylalkyl), and 3-10 memberedheterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms inwhich the heterocycloalkyl is optionally substituted by 1-6 R¹⁹.

Embodiment 143

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁴⁹), —NH(5-6 membered heterocycloalkyl),—NH(6-10 membered heterocycloalkylalkyl), and 5-10 memberedheterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms inwhich the heterocycloalkyl is optionally substituted by 1-6 R¹⁹.

Embodiment 144

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁴⁹), —NH(5-6 membered heterocycloalkyl),—NH(6-10 membered heterocycloalkylalkyl), and 5-9 memberedheterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms inwhich the heterocycloalkyl is optionally substituted by 1-6 R¹⁹.

Embodiment 145

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁴⁹), —NH(5-6 membered heterocycloalkyl),—NH(6-10 membered heterocycloalkylalkyl), and 5-6 memberedheterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms inwhich the heterocycloalkyl is optionally substituted by 1-6 R¹⁹.

Embodiment 146

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁴⁹), —NH(5-6 membered heterocycloalkyl),—NH(6-10 membered heterocycloalkylalkyl), and 5-10 memberedheterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms inwhich the heterocycloalkyl is optionally substituted by 1 or 2 memberschosen from C₁₋₆alkyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyloptionally substituted by 1-3 R³⁹, C₆₋₁₁aryl optionally substituted by1-3 R³⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R³⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, halogen, —CN,—C(═O)OR³, —C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰.

Embodiment 147

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁴⁹), —NH(5-6 membered heterocycloalkyl),—NH(6-10 membered heterocycloalkylalkyl), and 5-10 memberedheterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms inwhich the heterocycloalkyl is optionally substituted by 1 or 2 memberschosen from C₁₋₆alkyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyl,C₆₋₁₁aryl, C₇₋₁₆arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R³⁹, 5-10 memberedheterocycloalkyl, halogen, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³,—NR³⁴C(═O)OR³⁰, and —OR³⁰.

Embodiment 148

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁴⁹), —NH(5-6 membered heterocycloalkyl),—NH(6-10 membered heterocycloalkylalkyl), and 5-6 memberedheterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms inwhich the heterocycloalkyl is optionally substituted by 1 or 2 memberschosen from C₁₋₆alkyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyl,C₆₋₁₁aryl, C₇₋₁₆arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R³⁹, 5-10 memberedheterocycloalkyl, halogen, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³,—NR³⁴C(═O)R³⁰, and —OR³⁰.

Embodiment 149

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(C₇₋₁₁arylalkyl),—NH(5-6 membered heterocycloalkyl), —NH(6-10 memberedheterocycloalkylalkyl), and 5-6 membered heterocycloalkyl consisting ofcarbon atoms and 1 or 2 nitrogen atoms in which the heterocycloalkyl isoptionally substituted by 1 or 2 members chosen from C₁₋₆alkyloptionally substituted by 1-6 halogen, halogen, —CN, —C(═O)OR³⁰,—C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰

Embodiment 150

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(5-6 memberedheterocycloalkyl), —NH(6-10 membered heterocycloalkylalkyl), and 5-6membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogenatoms in which the heterocycloalkyl is optionally substituted by 1 or 2members chosen from C₁₋₆alkyl optionally substituted by 1-6 halogen,halogen, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, and—OR³⁰.

Embodiment 151

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(5-6 memberedheterocycloalkyl), and 5-6 membered heterocycloalkyl consisting ofcarbon atoms and 1 or 2 nitrogen atoms in which the heterocycloalkyl isoptionally substituted by 1 or 2 members chosen from C₁₋₆alkyloptionally substituted by 1-6 halogen, halogen, —CN, and —OH.

Embodiment 152

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(C₇₋₁₁arylalkyl),—NH(5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2nitrogen atoms), —NH(6-10 membered heterocycloalkylalkyl consisting ofcarbon atoms and 1 or 2 nitrogen atoms), and 5-6 memberedheterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms inwhich the heterocycloalkyl is optionally substituted by 1 or 2 memberschosen from C₁₋₆alkyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyl,C₆₋₁₁aryl, C₇₋₁₆arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R³⁹, 5-10 memberedheterocycloalkyl, halogen, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³,—NR³⁴C(═O)R³, and —OR³⁰.

Embodiment 153

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(benzyl), —NH(5-6membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogenatoms), —NH(6-10 membered heterocycloalkylalkyl consisting of carbonatoms and 1 or 2 nitrogen atoms), and 5-6 membered heterocycloalkylconsisting of carbon atoms and 1 or 2 nitrogen atoms in which theheterocycloalkyl is optionally substituted by 1 or 2 members chosen fromC₁₋₆alkyl optionally substituted by 1-6 halogen, halogen, —CN,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰.

Embodiment 154

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(5-6 memberedheterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms),—NH(6-10 membered heterocycloalkylalkyl consisting of carbon atoms and 1or 2 nitrogen atoms), and 5-6 membered heterocycloalkyl consisting ofcarbon atoms and 1 or 2 nitrogen atoms in which the heterocycloalkyl isoptionally substituted by 1 or 2 members chosen from C₁₋₆alkyloptionally substituted by 1-6 halogen, halogen, —CN, —C(═O)OR³⁰,—C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰.

Embodiment 155

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(5-6 memberedheterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms),and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2nitrogen atoms in which the heterocycloalkyl is optionally substitutedby 1 or 2 members chosen from C₁₋₆alkyl optionally substituted by 1-6halogen, halogen, —CN, and —OH.

Embodiment 156

The compound of any of Embodiments 1-3, wherein X is chosen from—NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹) and —NH(5-6 memberedheterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogen atoms).

Embodiment 200

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰, —C(═NR²⁵)NR²²R²³,—C(═NOH)NR²²R²³, —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰, —C(═NNR²⁴C(═O)R²¹)R²⁰,—C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂, —NR²²R²³,—NR²⁴NR²²R²³, —N═NR²⁴, NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰,NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³,—NR²⁴C(═O)NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰, —NR²⁴C(═NR²⁵)NR²²R²³,—NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰, —NR²⁴C(═S)OR²⁰,—NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —NR⁴P(═O)R⁷⁸R⁷⁸,—NR²⁴P(═O)(NR²²R²³)(N²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²⁰),—NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR²²R²³)(NR²²)(NR²³), —SP(═O)(OR²⁰)(OR²⁰),—SP(═O)(SR²⁰)(SR²⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²R²³)(NR²²R²³),—P(═O)(OR²⁰)(OR²⁰), and —P(═O)(SR²⁰)(SR²⁰); or R and R⁸ can, togetherwith the atoms linking them, form a C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 201

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═)OR²¹, NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)₂R²⁰,—OS(═O)²⁰R²⁰, OS(═O)₂NR²²R²³, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R⁷and R⁸ can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹.

Embodiment 202

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by1-6 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)OR²¹, —NR24C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═)₂R²⁰,OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R⁷and R⁸ can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 203

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-4R¹⁹, C₂₋₆alkenyl optionally substituted by 1-4 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-4 R¹⁹, C₆₋₁₀aryl optionally substituted by1-4 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-4 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-4 R¹⁹, C₄₋₈cycloalkylalkyloptionally substituted by 1-4 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-4 R¹⁹, 4-8 membered heterocycloalkylalkyloptionally substituted by 1-4 R¹⁹, 5-6 membered heteroaryl optionallysubstituted by 1-4 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-4 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,NR²⁴C(═)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═)OR²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R⁷and R⁸ can, together with the atoms linking them, form a C₆₋₁₀aryloptionally substituted by 1-4 R¹⁹, C₃₋₇cycloalkyl optionally substitutedby 1-4 R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-4R¹⁹ or a 5-6 membered heteroaryl optionally substituted by 1-4 R¹⁹.

Embodiment 204

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, C₄₋₈cycloalkylalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 4-8 membered heterocycloalkylalkyloptionally substituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —S(═)_(n)R²⁰ and —S(═O)₂NR²²R²³; or R⁷and R⁸ can, together with the atoms linking them, form a C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substitutedby 1-3 R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3R¹⁹ or a 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 205

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, C₄₋₈cycloalkylalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 4-8 membered heterocycloalkylalkyloptionally substituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, NR²⁴C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰,—OC(═O)NR²²R²³, —OS(═O)₂R²⁰, OS(═O)₂NR²²R²³, —S(═O)_(n)R²⁰, and—S(═O)₂NR²²R²³; or R⁷ and R⁸ can, together with the atoms linking them,form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-6 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 206

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇11arylalkyl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹, C₄₋₈cycloalkylalkyl optionallysubstituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹, 4-8 membered heterocycloalkylalkyl optionallysubstituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionally substitutedby 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted by 1-3R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰,—NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;or R⁷ and R⁸ can, together with the atoms linking them, form a C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substitutedby 1-3 R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3R¹⁹ or a 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 207

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₆₋₁₀aryl, C₇₋₁₁arylalkyl, C₃₋₇cycloalkyl, C₄₋₈cycloalkylalkyl, 3-7membered heterocycloalkyl, 4-8 membered heterocycloalkylalkyl, 5-6membered heteroaryl, 6-21 membered heteroarylalkyl, halogen, —CN,—C(═O)R²⁰, —C(═)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰,—NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²,R²³; or R⁷ and R⁸ can, together with the atoms linking them, form aC₆₋₁₀aryl, C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl or a 5-6membered heteroaryl.

Embodiment 208

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, C₄₋₈cycloalkylalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 4-8 membered heterocycloalkylalkyloptionally substituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; orR⁷ and R⁸ can, together with the atoms linking them, form a C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substitutedby 1-3 R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3R¹⁹ or a 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 209

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R⁷ and R⁸ can, together with theatoms linking them, form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, 3-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 210

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R⁷ and R⁸ can, together with theatoms linking them, form a C₃₋₇cycloalkyl optionally substituted by 1-3R¹⁹, or a 3-7 membered heterocycloalkyl optionally substituted by 1-3R¹⁹.

Embodiment 211

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl, C₂₋₆alkynyl, C₆₋₁₀aryl,C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl,halogen, —CN, —C(═O)R²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴S(═O)₂R²¹,—OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R⁷ and R⁸ can, togetherwith the atoms linking them, form a C₃₋₇cycloalkyl, or a 3-7 memberedheterocycloalkyl.

Embodiment 212

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, and —OR²⁰; or R⁷ and R⁸ can, togetherwith the atoms linking them, form a C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15membered heteroaryl optionally substituted by 1-15 R⁹.

Embodiment 213

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R¹⁹, halogen, —CN, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,and —OR²⁰; or R⁷ and R⁸ can, together with the atoms linking them, forma C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R¹⁹ or a 5-15 membered heteroaryloptionally substituted by 1-15 R¹⁹.

Embodiment 214

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R²³, —NR²⁴C(═O)R²⁰, and —OR²⁰; or R⁷ andR⁸ can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁹.

Embodiment 215

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R, —NR²⁴C(═O)R²⁰, and —OR²⁰; R⁸ is chosenfrom H, C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyloptionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)NR²²R²³, —NR²²R, —NR²⁴C(═O)R²⁰, and —OR²⁰; or R⁷ and R⁸can, together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹⁹or a 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 216

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³,—N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —NR²⁴P(═O)R⁷⁸R⁷⁸,—NR²⁴P(═O)NR²²R²³)(NR)(NR²³), —NR²⁴P(═)(OR²⁰)(OR²⁰),—NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, OC(═O)NR²²R²³,—OC(═)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³,—OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR²²R²³(NR²²R²³), —OP(═O)(OR²⁰)(OR²⁰),—OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰,—SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —SP(═O)R⁷⁸R⁷⁸,—SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰), —SP(═O)(SR²⁰)(SR²⁰),—P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²R)(NR²²R²³), —P(═O)(OR²⁰)(OR²⁰), and—P(═O)(SR²⁰)(SR²⁰); or R and R⁸ can, together with the atoms linkingthem, form a C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹.

Embodiment 217

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³,—NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, NR²⁴C(═O)OR²¹, NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN, —OC(═O)R²⁰,—OC(═O)NRR²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³,—Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰, —S(═O)₂R²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, and—S(═O)NR²²R²³; or R⁷ and R⁸ can, together with the atoms linking them,form a C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹ or a 5-10 membered heteroaryloptionally substituted by 1-6 R¹⁹.

Embodiment 218

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by1-6 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-10 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³,—NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²C(═)OR²¹, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN, —OC(═O)R²⁰,—OC(═O)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂NR²²R²³,—Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³,and —S(═O)NR²²R²³; or R⁷ and R⁸ can, together with the atoms linkingthem, form a C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 219

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by1-6 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OC(═O)R²⁰, —Si(R²⁴)₃, —S(═O)_(n)R²⁰,and —S(═O)₂NR²²R²³; or R⁷and R⁸ can, together with the atoms linking them, form a C₆₋₁₀aryloptionally substituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 220

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OC(═O)R²⁰, —Si(R²⁴)₃, —S(═O)_(n)R²⁰,and —S(═O)₂NR²²R²³.

Embodiment 221

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁹, halogen,—NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 222

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by1-6 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, halogen,—NR²²R²³, —NR²⁴C(═O)R²⁰, NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 222

The compound of any of Embodiments 1-156, wherein R⁷, R⁸, and R⁹ areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by1-6 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹, halogen,—NR²²R²³, —OR²⁰, and —S(═O)_(n)R²⁰

Embodiment 223

The compound of any of Embodiments 1-156 or 200-222, wherein R⁸ is notphenyl or morpholinyl.

Embodiment 224

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹, halogen, —CN, —C(═O)R²⁰,C(═)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R²⁰, and—S(═O)₂NR²²R²³; R⁸ is chosen from H, C₁₋₆alkyl optionally substituted by1-13 R¹⁹, halogen, —NR²²R²³, and —OR²⁰; and R⁹ is chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-15 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC,—NO₂, —NR²R²³, —NR²⁴C(═O)R²⁰, NR²⁴C(═O)OR²¹, NR²⁴C(═O)NR²²R²³,—NR₂₄S(═O)₂R²⁰, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, OC(═O)NR²²R²³,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 225

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰,(═)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R²⁰, and—S(═O)₂NR²²R²³; R⁸ is chosen from H, C₁₋₆alkyl optionally substituted by1-6 R¹⁹, halogen, —NR²²R²³, and —OR²⁰; and R⁹ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC,—NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—S(═O)_(n)R²⁰, and —S(═O)₂NR R²³.

Embodiment 226

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰,—(═)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R²⁰, and—S(═O)₂NR²²R²³; R⁸ is chosen from H, C₁₋₆alkyl optionally substituted by1-6 R¹⁹, halogen, —NR²²R²³, and —OR²⁰; and R⁹ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC,—NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 227

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰, —S(═)_(n)R²⁰, and—S(═O)₂NR²²R²³; R⁸ is chosen from H, C₁₋₆alkyl optionally substituted by1-6 R¹⁹, and halogen; and R⁹ is chosen from H, C₁₋₆alkyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²⁰, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OC(═O)R²⁰, —S(═)_(n)R²⁰ and —S(═O)₂NR²²R²³.

Embodiment 228

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,halogen, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰ and —OC(═O)R²⁰;R⁸ is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, andhalogen; and R⁹ is chosen from H, C₁₋₆alkyl optionally substituted by1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryloptionally substituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, C(═)OR²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 229

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₀-cycloalkyl optionally substituted by 1-6R¹⁹, halogen, —NR²²R²³, and —OR²⁰; R⁸ is chosen from H and halogen; andR⁹ is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-6 R¹⁹, halogen, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰, and—S(═O)_(n)R²⁰.

Embodiment 230

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₀-cycloalkyl optionally substituted by 1-6R¹⁹, halogen, —NR²²R²³, and —OR²⁰; R⁸ is chosen from H and halogen; andR⁹ is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-6 R¹⁹, halogen, —NR²²R²³, —OR²⁰, and —S(═O)_(n)R²⁰.

Embodiment 231

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀-cycloalkyl optionally substituted by 1-3R¹⁹, halogen, —NR²²R²³, and —OR²⁰; R⁸ is chosen from H and halogen; andR⁹ is chosen from H, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —NR²²R²³, —OR²⁰,and —S(═O)_(n)R²⁰.

Embodiment 232

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-3R¹⁹, halogen, —NR²²R²³, and —OR²⁰; R⁸ is chosen from H and halogen; andR⁹ is chosen from H, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-9 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —NR²²R²³, —OR²⁰,and —S(═O)_(n)R²⁰.

Embodiment 233

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R¹⁹, C₃₋₆cycloalkyl optionally substituted by 1-3R¹⁹, halogen, —NR²²R²³, and —OR²⁰; R⁸ is chosen from H and halogen; andR⁹ is chosen from H, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,phenyl optionally substituted by 1-3 R¹⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5, 6, or 9 membered heteroaryloptionally substituted by 1-3 R¹⁹, halogen, —NR²²R²³, —OR²⁰, and—S(═O)_(n)R²⁰.

Embodiment 234

The compound of any of Embodiments 1-156 or 200-233, wherein R⁸ is H.

Embodiment 235

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₀-cycloalkyl optionally substituted by 1-6R¹⁹, halogen, —NR²²R²³, and —OR²⁰; R⁸ is chosen from H and halogen; andR⁹ is chosen from H, C₁₋₆alkyl, C₂₋₆alkynyl optionally substituted by1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹, halogen, —NR²²R²³, —OR²⁰,and —SR²⁰.

Embodiment 236

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, —NR²²R²³, and —OR²⁰; R⁸ is chosenfrom H and halogen; and R⁹ is chosen from H, C₂₋₆alkynyl, C₆₋₁₀aryl,3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halogen,—NR²²R²³, —OR²⁰, and —SR²⁰.

Embodiment 237

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₃₋₆cycloalkyl, and —OR²⁰; R⁸ is chosen from H and halogen; and R⁹ ischosen from H, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5-9 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, halogen, —NR²²R²³, —OR²⁰, and —SR²⁰.

Embodiment 238

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₃₋₆cycloalkyl, and —OR²⁰; R⁸ is chosen from H and halogen; and R⁹ ischosen from H, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, phenyloptionally substituted by 1-3 R¹⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5, 6, or 9 membered heteroaryloptionally substituted by 1-3 R¹⁹, halogen, —NR²²R²³, —OR²⁰, and —SR²⁰.

Embodiment 239

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₃₋₆cycloalkyl, and —O(C₁₋₆alkyl); R⁸ is chosen from H and halogen; andR⁹ is chosen from H, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,phenyl optionally substituted by 1-3 R¹⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5, 6, or 9 membered heteroaryloptionally substituted by 1-3 R¹⁹, halogen, —NR²²R²³, —OR²⁰, and —SR²⁰.

Embodiment 240

The compound of any of Embodiments 1-156, wherein R⁷ is

chosen from H, C₃₋₆cycloalkyl, and —OR²⁰; R⁸ is H; and R⁹ is H.

Embodiment 241

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,C₃₋₆cycloalkyl, and —O(C₁₋₆alkyl); R⁸ is H; and R⁹ is H.

Embodiment 242

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,cyclopropyl, and —O(C₁₋₆alkyl); R⁸ is chosen from H and halogen; and R⁹is chosen from H, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, phenyloptionally substituted by 1-3 R¹⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5, 6, or 9 membered heteroaryloptionally substituted by 1-3 R¹⁹, halogen, —NR²²R²³, —OR²⁰, and —SR²⁰.

Embodiment 243

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,cyclopropyl, and —OR²⁰; R⁸ is H; and R⁹ is H.

Embodiment 244

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,cyclopropyl, and —O(C₁₋₆alkyl); R⁸ is H; and R⁹ is H.

Embodiment 245

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,cyclopropyl, and —O(CH₃); R⁸ is H; and R⁹ is H.

Embodiment 246

The compound of any of Embodiments 1-156, wherein R⁷ is H; R⁸ is H; andR⁹ is H.

Embodiment 247

The compound of any of Embodiments 1-156, wherein R⁷ is cyclopropyl; R⁸is H; and R⁹ is H.

Embodiment 248

The compound of any of Embodiments 1-156, wherein R⁷ is —O(CH₃); R⁸ isH; and R⁹ is H.

Embodiment 249

The compound of any of Embodiments 1-156, wherein R⁷ is chosen from H,cyclopropyl, and —O(C₁₋₆alkyl); R⁸ is chosen from H and halogen; and R⁹is chosen from H, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, phenyloptionally substituted by 1-3 R¹⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5, 6, or 9 membered heteroaryloptionally substituted by 1-3 R¹⁹, halogen, —NR²²R²³, —OR²⁰, and —SR²⁰.

Embodiment 250

The compound of any of Embodiments 1-156, wherein R⁷ is

chosen from H, C₃₋₆cycloalkyl, and —O(CH₃); R⁸ is chosen from H andhalogen; and R⁹ is chosen from H, C₂₋₆alkynyl optionally substituted by1-3 R¹⁹, phenyl optionally substituted by 1-3 R¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5, 6, or 9 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —NR²²R²³, —OR²⁰,and —SR²⁰.

Embodiment 300

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R²,R¹³, R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionallysubstituted by 1-6 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-6 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰,—C(═NR²⁵)NR²²R²³, —C(═NOH)NR²²R²³, —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰,—C(═NNR²⁴C(═O)R²¹)R²⁰, —C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂,—NR²²R²³, —NR²⁴NR²²R²³, N═NR²⁴, NR²⁴OR²⁶, NR²⁴C(═O)R²⁰,—NR²C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰,—NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—NR²⁴P(═O)R⁷⁸R⁷⁸, —NR²⁴P(═O)NR²²R²³)(NR²²R²³), —NR²⁴P(═)(OR²⁰)(OR²⁰),—NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(R²⁰),—SP(═O)(SR²⁰)(SR²⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²R²³)(NR²²R²³),—P(═O)(OR²⁰)(OR²⁰), and —P(═O)(SR²⁰)(SR²⁰); or either or both of R¹² andR¹³, and/or R¹⁴ and R¹⁵, can, together with the atoms linking them, forma C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹ or a 5-15 membered heteroaryloptionally substituted by 1-6 R¹⁹.

Embodiment 301

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹³, R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionallysubstituted by 1-6 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-6 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³,—N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —NR²⁴P(═O)R⁷⁸R⁷⁸,—NR²⁴P(═O)(NR²²R²³)(NR²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²⁰), —OR²⁰, —OCN,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —OP(═O)R⁷⁸R⁷⁸, OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷,—S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²(NR²²)(NR²³),and —P(═O)(OR²⁰)(OR²⁰); or either or both of R¹² and R¹³, and/or R¹⁴ andR¹⁵, can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 302

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹³, R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionallysubstituted by 1-6 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —N═NR,—NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NRR²³, —NR²⁴P(═O)R⁷⁸R⁷⁸,—NR²⁴P(═O)(NR²²R²³)(N²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²⁰), —OR²⁰, —OCN,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷,—S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²R²³)(NR²²R²³),and —P(═O)(OR²⁰)(OR²⁰); or either or both of R¹² and R¹³, and/or R¹⁴ andR¹⁵, can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 303

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹³, R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionallysubstituted by 1-6 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, NR²⁴C(═)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰,−SO₃R²⁷, —S(═O)₂NR R², —S(═O)NR²²R²³, —P(═O)R⁷⁸R⁷⁸,—P(═O)(NR²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰); or either or both ofR¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atoms linkingthem, form a C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 304

The compound of any of Embodiments 1, 2, 4-156, or 200-250,

wherein R¹², R¹³, R¹⁴, and R¹⁵ are independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-15 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, NR²⁴C(═)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²⁰,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, OC(═O)NR²²R²³, —OC(═O)OR²⁰,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²R²³(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰); or eitheror both of R¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atomslinking them, form a C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 305

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹³, R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —OC(═O)NR R²³, —OC(═O)OR²⁰,S(═O)_(n)R²⁰S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰); oreither or both of R¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together withthe atoms linking them, form a C₆₋₁₀aryl optionally substituted by 1-3R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 306

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹³, R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₇ cycloalkyl optionally substituted by 1-3R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —S(═O)_(n)R²⁰,—S(═O)₂R²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —P(O)R⁷⁸R⁷⁸,—P(═O)(NR²²R²³)(NR²²R²³), and —P(═O)(OR²⁰)(OR²⁰); or either or both ofR¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atoms linkingthem, form a C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-6 membered heteroaryloptionally substituted by 1-3 R¹⁹.

Embodiment 307

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹³, R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)N²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or either orboth of R¹² and R¹³, and/or R¹⁴ and R¹⁵, can, together with the atomslinking them, form a C₆₋₁₁ aryl optionally substituted by 1-3 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 308

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹³, R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, 3-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or either or both of R¹² and R¹³,and/or R¹⁴ and R¹⁵, can, together with the atoms linking them, form aphenyl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹ or a 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 309

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, and halogen; R¹³ is chosen from H, C₁₋₆alkyloptionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₁aryloptionally substituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, C(═O)OR²⁰, —C(═O)NR²²R²³, —NC,—NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —N═NR²⁴, —NR₂₄OR²⁶, —NR²C(═O)R²⁰,NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰, NR⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰,—NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—NR²⁴P(═O)R⁷⁸R⁷⁸, —NR²⁴P(═O)(NR²²R²³(NR²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²⁰),—NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═)OR²⁰, —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷,—S(═O)₂NR²²R²³, and —S(═O)NR²²R²³; or either or both of R¹² and R¹³,and/or R¹⁴ and R¹⁵, can, together with the atoms linking them, form aC₆₋₁₁aryl optionally substituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 310

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, and halogen; R¹³ is chosen from H, C₁₋₆alkyloptionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryloptionally substituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC,—NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰,—NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—NR²⁴P(═O)R⁷⁸R⁷⁸, —NR²⁴P(═O)NR²²R²³)(NR²²)(NR²³), —NR²⁴P(═)(OR²⁰)(OR²⁰),—NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰, —S(═O)₂R²⁰, —SO₃R²⁷,—S(═O)₂NR²²R²³, and —S(═O)NR²²R²³; or R¹² and R¹³ can, together with theatoms linking them, form a C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 311

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, and halogen; R¹³ is chosen from H, C₁₋₆alkyloptionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryloptionally substituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC,—NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN, —OC(═O)R²⁰, OC(═O)NR²²R²³, —OC(═O)OR²⁰,—SCN, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R¹² and R¹³ can, togetherwith the atoms linking them, form a C₆10aryl optionally substituted by1-6 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-10membered heteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 312

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, and halogen; R¹³ is chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, 3-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —NR²⁴OR²⁶,—NR²⁴C(═O)R²⁰, —NR²⁴C(═)OR²¹, —NR²C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R²⁰, and—S(═O)₂NR²²R²³; or R¹² and R¹³ can, together with the atoms linkingthem, form a phenyl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-10 membered heteroaryloptionally substituted by 1-6 R¹⁹.

Embodiment 313

The compound of any of Embodiments 1, 2, 4-156, or 200-250,

wherein R¹², R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, and halogen; R¹³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, phenyl optionallysubstituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionally substitutedby 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴NR²²R²³, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹,NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R¹² and R¹³ can, together with theatoms linking them, form a phenyl optionally substituted by 1-3 R¹⁹ or a5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 314

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²and R¹⁴ are H; R¹⁵ is chosen from H, C₁₋₆alkyl optionally substituted by1-3 R¹⁹, and halogen; R¹³ is chosen from H, C₁₋₆alkyl optionallysubstituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkynyl optionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³,—NR²⁴NR²²R²³, —NR₂₄OR²⁶, —NR²⁴C(═O)R²⁰, NR^(c)(═O)C(═O)R²⁰,—NR²⁴C(═)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, —OCN, —OC(═O)R²⁰,—OC(═O)NR²²R²³, —OC(═O)OR²⁰, —SCN,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R¹² and R¹³ can, together with theatoms linking them, form a C₆10aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 315

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²and R¹⁴ are H; R¹⁵ is chosen from H, C₁₋₆alkyl optionally substituted by1-3 R¹⁹, and halogen; R¹³ is chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3 R¹⁹,C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, 3-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³, NR²⁴OR²⁶,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR R²³, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;or R¹² and R¹³ can, together with the atoms linking them, form a phenyloptionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substitutedby 1-3 R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3R¹⁹ or a 5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 316

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²and R¹⁴ are H; R¹⁵ is chosen from H and halogen; R¹³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, phenyl optionallysubstituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionally substitutedby 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴NR²²R²³, —NR²OR²⁶, —NR²⁴C(═O)R²⁰, NR²⁴C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰,—OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R¹² and R¹³ can,together with the atoms linking them, form a phenyl optionallysubstituted by 1-3 R¹⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 317

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, and halogen; R¹³ is chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, 3-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —NR²⁴OR²⁶,—NR²⁴C(═O)R²⁰, —NR₂₄C(═)OR²¹, —NR²C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR R²³, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³;or R¹² and R¹³ can, together with the atoms linking them, form a phenyloptionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substitutedby 1-3 R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3R¹⁹ or a 5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 318

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R¹⁹, and halogen; R¹³ is chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³,—NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R²⁰,and —S(═O)₂NR²R²³; or R¹² and R¹³ can, together with the atoms linkingthem, form a phenyl optionally substituted by 1-3 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 319

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, halogen,—CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³,—NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, NR²⁴C(═)OR²¹, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R²⁰ and—S(═O)₂NR²²R²³; or R¹² and R¹³ can, together with the atoms linkingthem, form a phenyl optionally substituted by 1-3 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 320

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, halogen,—CN, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹,NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R¹² and R¹³ can, together with theatoms linking them, form a phenyl optionally substituted by 1-3 R¹⁹ or a5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 321

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, halogen,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, and —NR²⁴S(═O)₂NR²²R²³; or R¹² andR¹³ can, together with the atoms linking them, form a phenyl optionallysubstituted by 1-3 R¹⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 322

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, halogen,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, and —NR²⁴S(═O)₂NR²²R²³; or R¹² andR¹³ can, together with the atoms linking them, form a phenyl optionallysubstituted by 1-3 R¹⁹ or a 5-6 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 323

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, and—NR²⁴S(═O)₂NR²²R²³; or R¹² and R¹³ can, together with the atoms linkingthem, form a phenyl optionally substituted by 1-3 R¹⁹ or a 5-6 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 324

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, —NR²²R²³, —NR²⁴C(═O)R²⁰, NR²⁴C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, and —NR²⁴S(═O)₂NR²²R²³; or R¹² andR¹³ can, together with the atoms linking them, form a 5-6 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 325

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, togetherwith the atoms linking them, form a 5-6 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 326

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, togetherwith the atoms linking them, form a 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 327

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²and R¹⁴ are H; R¹⁵ is chosen from H and halogen; R¹³ is chosen from H,—NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atomslinking them, form a 5-6 membered heteroaryl optionally substituted by1-3 R¹⁹.

Embodiment 328

The compound of any of Embodiments 1, 2, 4-156, or 200-250,

wherein R¹⁴ and R¹⁵ are H; R¹² is chosen from H and halogen; R¹³ ischosen from H, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, togetherwith the atoms linking them, form a 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 329

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, togetherwith the atoms linking them, form a 5 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 330

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²and R¹⁴ are H; R¹⁵ is chosen from H and halogen; R¹³ is chosen from H,—NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atomslinking them, form a 5 membered heteroaryl optionally substituted by 1-3R¹⁹.

Embodiment 331

The compound of any of Embodiments 1, 2, 4-156, or 200-250,

wherein R¹⁴ and R¹⁵ are H; R¹² is chosen from H and halogen; R¹³ ischosen from H, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, togetherwith the atoms linking them, form a 5 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 332

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, togetherwith the atoms linking them, form a 5 membered heteroaryl optionallysubstituted by 1-2 R¹⁹.

Embodiment 333

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²and R¹⁴ are H; R¹⁵ is chosen from H and halogen; R¹³ is chosen from H,—NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atomslinking them, form a 5 membered heteroaryl optionally substituted by 1-2R¹⁹.

Embodiment 334

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴and R¹⁵ are H; R¹² is chosen from H and halogen; R¹³ is chosen from H,—NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atomslinking them, form a 5 membered heteroaryl optionally substituted by 1-2R¹⁹.

Embodiment 335

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, togetherwith the atoms linking them, form a 5 membered heteroaryl optionallysubstituted by 1 R¹⁹.

Embodiment 336

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²and R¹⁴ are H; R¹⁵ is chosen from H and halogen; R¹³ is chosen from H,—NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atomslinking them, form a 5 membered heteroaryl optionally substituted by 1R¹⁹.

Embodiment 337

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴and R¹⁵ are H; R¹² is chosen from H and halogen; R¹³ is chosen from H,—NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atomslinking them, form a 5 membered heteroaryl optionally substituted by 1R¹⁹.

Embodiment 338

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴is H; R¹² and R¹⁵ are independently chosen from H and halogen; R¹³ ischosen from H, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, togetherwith the atoms linking them, form a pyrrolyl ring optionally substitutedby 1 R¹⁹.

Embodiment 339

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²and R¹⁴ are H; R¹⁵ is chosen from H and halogen; R¹³ is chosen from H,—NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atomslinking them, form a pyrrolyl ring optionally substituted by 1 R¹⁹.

Embodiment 340

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹⁴and R¹⁵ are H; R¹² is chosen from H and halogen; R¹³ is chosen from H,—NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atomslinking them, form a pyrrolyl ring optionally substituted by 1 R¹⁹.

Embodiment 341

The compound of any of Embodiments 300-340, wherein R¹⁴ is H.

Embodiment 342

The compound of any of Embodiments 300-341, wherein R¹⁵ is H.

Embodiment 343

The compound of any of Embodiments 300-342, wherein R¹² is H.

Embodiment 344

The compound of any of Embodiments 300-343, wherein R¹³ is H.

Embodiment 345

The compound of any of Embodiments 300-340, wherein R¹⁴ and R¹⁵ are H.

Embodiment 346

The compound of any of Embodiments 300-340, wherein R¹² are R¹⁵ are H.

Embodiment 347

The compound of any of Embodiments 300-340, wherein R¹², R¹⁴ and R¹⁵ areH.

Embodiment 348

The compound of any of Embodiments 300-340, wherein R¹² are R¹⁴ are H.

Embodiment 349

The compound of any of Embodiments 1, 2, 4-156, 200-250, or 300-340,wherein R¹², R¹³, R¹⁴, and R¹⁵ are H.

Embodiment 350

The compound of any of Embodiments 300-342, wherein R¹² and R¹³,together with the atoms linking them, form a 5 membered heteroaryloptionally substituted by 1-2 R¹⁹

Embodiment 351

The compound of any of Embodiments 300-342, wherein R¹² and R¹³,together with the atoms linking them, form a 5 membered heteroaryloptionally substituted by 1 R¹⁹.

Embodiment 352

The compound of any of Embodiments 300-342, wherein R¹² and R¹³,together with the atoms linking them, form a pyrrolyl ring optionallysubstituted by 1 R¹⁹.

Embodiment 353

The compound of any of Embodiments 300-342, wherein R¹² and R¹³,together with the atoms linking them, form a pyrrolyl ring.

Embodiment 354

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, C₇₋₁₆arylalkyl optionallysubstituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-6 R¹⁹, halogen, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, or a 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 355

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, C₇₋₁₆arylalkyl optionallysubstituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-6 R¹⁹, halogen, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-6 R¹⁹, 5-10 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, or a 5-10 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 356

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, C₇₋₁₆arylalkyl optionallysubstituted by 1-3 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-3 R¹⁹, halogen, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-3 R¹⁹, 5-10 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹, or a 5-10 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.

Embodiment 357

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, halogen, —NR²²R²³, and—NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, or a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 358

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, halogen, —NR²²R²³, and—NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a phenyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ in which theheterocycloalkyl contains carbon atoms and 1 or 2 nitrogen atoms, or a5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹ in which theheteroaryl contains carbon atoms and 1 or 2 nitrogen atoms.

Embodiment 359

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, halogen, —NR²²R²³, and—NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a phenyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ in which theheterocycloalkyl contains carbon atoms and 1 nitrogen atom, or a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹ in which theheteroaryl contains carbon atoms and 1 nitrogen atom.

Embodiment 360

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NR²²R²³, and—NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, or a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 361

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NR²²R²³, and—NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a phenyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ in which theheterocycloalkyl contains carbon atoms and 1 or 2 nitrogen atoms, or a5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹ in which theheteroaryl contains carbon atoms and 1 or 2 nitrogen atoms.

Embodiment 362

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NR²²R²³, andNR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a phenyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ in which theheterocycloalkyl contains carbon atoms and 1 nitrogen atom, or a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹ in which theheteroaryl contains carbon atoms and 1 nitrogen atom.

Embodiment 363

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NHR²³, and —NHC(═O)R²⁰;or R¹² and R¹³ can, together with the atoms linking them, form aC₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, or a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 364

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NHR²³, and —NHC(═O)R²⁰;or R¹² and R¹³ can, together with the atoms linking them, form a phenyloptionally substituted by 1-3 R¹⁹, 5-10 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ in which the heterocycloalkyl containscarbon atoms and 1 or 2 nitrogen atoms, or a 5-10 membered heteroaryloptionally substituted by 1-3 R¹⁹ in which the heteroaryl containscarbon atoms and 1 or 2 nitrogen atoms.

Embodiment 365

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NHR²³, and —NHC(═O)R²⁰;or R¹² and R¹³ can, together with the atoms linking them, form a phenyloptionally substituted by 1-3 R¹⁹, 5-10 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ in which the heterocycloalkyl containscarbon atoms and 1 nitrogen atom, or a 5-10 membered heteroaryloptionally substituted by 1-3 R¹⁹ in which the heteroaryl containscarbon atoms and 1 nitrogen atom.

Embodiment 366

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NHR²³, and —NHC(═O)R²⁰;or R¹² and R¹³ can, together with the atoms linking them, form a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 367

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NHR²³, and —NHC(═O)R²⁰;or R¹² and R¹³ can, together with the atoms linking them, form a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹ in which theheteroaryl contains carbon atoms and 1 or 2 nitrogen atoms.

Embodiment 368

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NHR²³, and —NHC(═O)R²⁰;or R¹² and R¹³ can, together with the atoms linking them, form a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹ in which theheteroaryl contains carbon atoms and 1 nitrogen atom.

Embodiment 369

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H and —NHR²³; or R¹² and R¹³can, together with the atoms linking them, form a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 370

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H and —NHR²³; or R¹² and R¹³can, together with the atoms linking them, form a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹ in which the heteroarylcontains carbon atoms and 1 or 2 nitrogen atoms.

Embodiment 371

The compound of any of Embodiments 1, 2, 4-156, or 200-250, wherein R¹²,R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H and —NHR²³; or R¹² and R¹³can, together with the atoms linking them, form a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹ in which the heteroarylcontains carbon atoms and 1 nitrogen atom.

Embodiment 400

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by1-6 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, C(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰, —C(═NR²⁵)NR²²R²³,—C(═NOH)NR²²R²³, —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰, —C(═NNR²⁴C(═O)R²¹)R²⁰,—C(═NNR²⁴C(═)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³,—N═NR²⁴, —NR²⁴⁰R²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹,—NR²⁴C(═O)C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰,—NR²⁴C(═O)NR²⁴C(═O)OR²⁰, —NR²⁴C(═NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²,—NR²⁴C(═S)R²⁰, —NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —NR²⁴P(═O)R⁷⁸R⁷⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³),—NR²⁴P(═O)(OR²⁰)(OR²⁰), —NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰,—OC(═O)NR²²R²³, —OC(═O)OR²⁰, OC(═NR²⁵)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, OP(═O)R⁷R⁷, —OP(═O)(NR²²R²³)(NR²²R²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂R²⁰, —SO₃R²⁷, —S(═O)₂NR²R²³, —S(═O)NR²²R²³,—SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(R²⁰),—SP(═O)(SR²⁰)(SR²⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²R²³)(NR²²R²³),—P(═O)(OR²⁰)(OR²⁰), and —P(═O)(SR²⁰)(SR²⁰); or any of R^(a) and R^(b),R^(a) and R^(c), R^(a) and R^(e), R^(a) and R^(g), R^(b) and R^(d),R^(b) and R^(f), R^(b) and R^(h), R and R^(d), R and R^(e), R^(c) andR^(g), R^(d) and R^(f), R^(d) and R^(h), R^(e) and R^(f), R^(e) andR^(g), R^(f) and R^(h), and R^(g) and R^(h) can, together with the atomslinking them, form a C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 401

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by1-6 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, 6-21 membered heteroarylalkyl optionallysubstituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, C(═O)C(═O)R²⁰, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³,—N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═)OR²¹,—NR²C(═O)C(═)OR²¹, —NR²⁴C(═O)NR²²R²³, NR²⁴C(═O)NR²⁴C(═O)R²⁰,—NR²⁴C(═O)NR²⁴C(═O)OR²⁰, —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —NR²⁴P(═O)R⁷⁸R⁷⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³),—NR²⁴P(═O)(OR²⁰)(OR²⁰), —NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰,—OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —OP(═O)R⁷⁸R⁷⁸,—OP(═O)(NR²²R²³)(NR²²R²³)(NR²), OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²)(SR²⁰),—Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³,—S(═O)NR²²R²³, —SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR²²R²³)(NR²²R²³),—SP(═O)(OR²⁰)(OR²⁰), —SP(═O)(SR²⁰)(SR²⁰), —P(═O)R⁷⁸R⁷⁸,—P(═O)(NR²²R²³)(NR²²R²³), —P(═O)(OR²⁰)(OR²⁰), and —P(═O)(SR²⁰)(SR²⁰); orany of R^(a) and R^(b), R^(a) and R^(c), R^(a) and R^(e), R^(a) andR^(g), R^(b) and R^(d), R^(b) and R^(f), R^(b) and R^(h), R and R^(d), Rand R^(e), R^(c) and R^(g), R^(d) and R^(f), R^(d) and R^(h), R^(e) andR^(f), R^(e) and R^(g), R^(f) and R^(h), and R^(g) and R^(h) can,together with the atoms linking them, form a C₆₋₁₁aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹ ora 5-15 membered heteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 402

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by1-6 R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, −C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —NR²⁴OR²⁶,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰,—S(═O)₂OR²⁰, —SO₃R²⁷, and —S(═O)₂NR²²R²³; or any of R^(a) and R^(b),R^(a) and R^(e), R^(a) and R^(e), R^(a) and R^(g), R^(b) and R^(d),R^(b) and R^(f), R^(b) and R^(h), R^(c) and R^(d), R^(c) and R^(e),R^(c) and R^(g), R^(d) and R^(f), R^(d) and R^(h), R^(e) and R^(f),R^(e) and R^(f), R^(f) and R^(h), and R^(g) and R^(h) can, together withthe atoms linking them, form a C₆₋₁₁aryl optionally substituted by 1-6R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 403

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by1-6 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —NR²⁴OR²⁶,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰,—OS(═O)₂R²⁰, —OS(═O)₂NR²²R²³, —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰,—S(═O)₂R²⁰, —SO₃R²⁷, and —S(═O)₂NR²²R²³; or any of R^(a) and R^(b),R^(a) and R^(c), R^(a) and R^(e), R^(a) and R^(g), R^(b) and R^(d),R^(b) and R^(f), R^(b) and R^(h), R^(c) and R^(d), R^(c) and R^(e),R^(c) and R^(g), R^(d) and R^(f), R^(d) and R^(h), R^(e) and R^(f),R^(e) and R^(g), R^(f) and R^(h), and R^(g) and R^(h) can, together withthe atoms linking them, form a C₆₋₁₀aryl optionally substituted by 1-6R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 404

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by1-6 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, OC(═O)R²⁰,—OC(═O)NR²²R²³, —OC(═O)OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or anyof R^(a) and R^(b), R^(a) and R^(e), R^(a) and R^(e), R^(a) and R^(g),R^(b) and R^(d), R^(b) and R^(f), R^(b) and R^(h), R and R^(d), R andR^(e), R^(c) and R^(g), R^(d) and R^(f), R^(d) and R^(h), R^(e) andR^(f), R^(e) and R^(g), R^(f) and R^(h), and R^(g) and R^(h) can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 405

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)OR²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, OC(═O)R²⁰,—OC(═O)NR²²R²³, —OC(═O)OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or anyof R^(a) and R^(b), R^(a) and R^(e), R^(a) and R^(e), R^(a) and R^(g),R^(b) and R^(d), R^(b) and R^(f), R^(b) and R^(h), R and R^(d), R andR^(e), R^(c) and R^(g), R^(d) and R^(f), R^(d) and R^(h), R^(e) andR^(f), R^(e) and R^(g), R^(f) and R^(h), and R^(g) and R^(h) can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 406

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(e), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R¹⁹, 5-10 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —S(═)_(n)R²⁰, and —S(═O)₂NR²²R²³.

Embodiment 407

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴S(═O)₂R²¹, —OR²⁰, —OC(═O)R²⁰, —OC(═O)OR²⁰, —S(═)_(n)R²⁰, and—S(═O)₂NR²²R²³.

Embodiment 408

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, halogen, —NO₂,—NR²²R²³, —NR²⁴C(═O)R²⁰, and —NR²⁴S(═O)₂R²¹

Embodiment 409

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —NR²⁴S(═O)₂R²¹.

Embodiment 410

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, —NR²²R²³, and—NR²⁴C(═O)R²⁰.

Embodiment 411

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, and C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 412

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, and benzyl optionally substituted by 1-3 R¹⁹.

Embodiment 413

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1 R¹⁹,and benzyl optionally substituted by 1 R¹⁹.

Embodiment 414

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1 R¹⁹,and benzyl.

Embodiment 415

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, methyl optionally substituted by 1 R¹⁹, andbenzyl optionally substituted by 1 R¹⁹.

Embodiment 416

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, methyl optionally substituted by 1 R¹⁹, andbenzyl.

Embodiment 417

The compound of any of Embodiments 400-416, wherein at least three ofR^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) are H.

Embodiment 418

The compound of any of Embodiments 400-416, wherein at least four ofR^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) are H.

Embodiment 419

The compound of any of Embodiments 400-416, wherein at least five ofR^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) are H.

Embodiment 420

The compound of any of Embodiments 400-416, wherein at least six ofR^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) are H.

Embodiment 421

The compound of any of Embodiments 400-416, wherein at least seven ofR^(a), R^(b), R^(e), R^(d), R^(e), R^(f), R^(g), and R^(h) are H.

Embodiment 422

The compound of any of Embodiments 400-416, wherein R^(a), R^(b) R^(c),R^(e), R^(f), R^(g), and R^(h) are H.

Embodiment 423

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-6 R¹⁹, C₄₋₁₇cycloalkylalkyl optionallysubstituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, 4-21 membered heterocycloalkylalkyl optionallysubstituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-6 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted by 1-6R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —C(═O)C(═O)R²⁰,—C(═NR²⁵)R²⁰, —C(═NR²⁵)NR²²R²³, —C(═NOH)NR²²R²³, —C(═NOR²⁶)R²⁰,—C(═NNR²²R²³)R²⁰, —C(═NNR²⁴C(═O)R²¹)R²⁰, —C(═NNR²⁴C(═O)OR²¹)R²⁰,—C(═S)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —N═NR²⁴, NR²⁴OR²⁶,NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═NR²⁵)NR²²R²³, —NR²⁴C(═O)C(═O)NR²²R²³, NR²⁴C(═S)R²⁰,—NR²⁴C(═S)OR²⁰, —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—NR²⁴P(═O)R⁷⁸R⁷⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²⁰),—NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)³, —SCN, —S(═O)nR²⁰,—S(═O)₂R²⁰, —SO³R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³, —SP(═O)R⁷⁸R⁷⁸,—SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(R²⁰), —SP(═O)(SR²⁰)(SR²⁰),—P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²R²³)(NR²²R²³), —P(═O)(OR²⁰)(OR²⁰), and—P(═O)(SR²⁰)(SR²⁰); or any of R^(a) and R^(b), R^(a) and R^(c), R^(a)and R^(e), R^(a) and R^(g), R^(b) and R^(d), R^(b) and R^(f), R^(b) andR^(h), R and R^(d), R and R^(e), R^(c) and R^(g), R^(d) and R^(f), R^(d)and R^(h), R^(e) and R^(f), R^(e) and R^(g), R^(f) and R^(h), and R^(g)and R^(h) can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.

Embodiment 424

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-6 R¹⁹, C₄₋₁₇cycloalkylalkyl optionallysubstituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹, 4-21 membered heterocycloalkylalkyl optionallysubstituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionally substitutedby 1-6 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted by 1-6R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —C(═O)C(═O)R²⁰,—NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,—NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰, NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—NR²⁴P(═O)R⁷⁸R⁷⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³), —NR²⁴P(═O)(OR²⁰)(OR²⁰),—NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³, —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰,—OS(═O)₂NR²²R²³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR²²R²³)(NR²²R²³),—OP(═O)(OR²⁰)(OR²⁰), —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN,—S(═O)_(n)R²⁰, —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,—SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰),—SP(═O)(SR²⁰)(SR²⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²R²³(NR²²R²³),—P(═O)(OR²⁰)(OR²⁰), and —P(═O)(SR(SR²⁰); or any of R^(a) and R^(b),R^(a) and R^(e), R^(a) and R^(e), R^(a) and R^(g), R^(b) and R^(d),R^(b) and R^(f), R^(b) and R^(h), R and R^(d), R and R^(e), R^(c) andR^(g), R^(d) and R^(f), R^(d) and R^(h), R^(e) and R^(f), R^(e) andR^(g), R^(f) and R^(h), and R^(g) and R^(h) can, together with the atomslinking them, form a C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 425

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-6 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-6 R¹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —NR²⁴OR²⁶,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰,—S(═O)₂OR²⁰, —SO₃R²⁷, and —S(═O)₂NR²²R²³; or any of R^(a) and R^(b),R^(a) and R^(c), R^(a) and R^(e), R^(a) and R^(g), R^(b) and R^(d),R^(b) and R^(f), R^(b) and R^(h), R and R^(d), R and R^(e), R^(c) andR^(g), R^(d) and R^(f), R^(d) and R^(h), R^(e) and R^(f), R^(e) andR^(g), R^(f) and R^(h), and R^(g) and R^(h) can, together with the atomslinking them, form a C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 426

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³, —NR²⁴OR²⁶,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²⁴C(═O)OR²⁰,—NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OCN,—OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OS(═O)R²⁰, —OS(═O)₂R²⁰,—OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³, —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰,—S(═O)₂OR²⁰, —SO₃R²⁷, and —S(═O)₂NR²²R²³; or any of R^(a) and R^(b),R^(a) and R^(e), R^(a) and R^(e), R^(a) and R^(g), R^(b) and R^(d),R^(b) and R^(f), R^(b) and R^(h), R^(c) and R^(d), R^(c) and R^(e),R^(c) and R^(g), R^(d) and R^(f), R^(d) and R^(h), R^(e) and R^(f),R^(e) and R^(g), R^(f) and R^(h), and R^(g) and R^(h) can, together withthe atoms linking them, form a C₆₋₁₀aryl optionally substituted by 1-6R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 427

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-6 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-6 R¹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or any of R^(a) andR^(b), R^(a) and R^(c), R^(a) and R^(e), R^(a) and R^(g), R^(b) andR^(d), R^(b) and R^(f), R^(b) and R^(h), R and R^(d), R and R^(e), R^(c)and R^(g), R^(d) and R^(f), R^(d) and R^(h), R^(e) and R^(f), R^(e) andR^(g), R^(f) and R^(h), and R^(g) and R^(h) can, together with the atomslinking them, form a C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁹.

Embodiment 428

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R¹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5-10 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or any of R^(a) andR^(b), R^(a) and R^(e), R^(a) and R^(e), R^(a) and R^(g), R^(b) andR^(d), R^(b) and R^(f), R^(b) and R^(h), R^(c) and R^(d), R^(c) andR^(e), R^(c) and R^(g), R^(d) and R^(f), R^(d) and R^(h), R^(e) andR^(f), R^(e) and R^(g), R^(f) and R^(h), and R^(g) and R^(h) can,together with the atoms linking them, form a C₆₋₁₀aryl optionallysubstituted by 1-3 R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.

Embodiment 429

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-3 R¹⁹, 5-10 membered heteroaryl optionally substitutedby 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,—NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —OC(═O)NR R²³, —OC(═O)OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR R²³

Embodiment 430

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰,—NR²⁴S(═O)₂R²¹, —OR²⁰, OC(═O)R²⁰, —OC(═O)OR²⁰, —S(═O)_(n)R²⁰, and—S(═O)₂NR²R²³.

Embodiment 431

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, halogen, —NO₂,—NR²²R²³, —NR²⁴C(═O)R²⁰, and —NR²⁴S(═O)₂R²¹.

Embodiment 432

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, —NR²²R²³,—NR²⁴C(═O)R²⁰, and —NR²⁴S(═O)₂R²¹.

Embodiment 433

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹, —NR²²R²³, and—NR²⁴C(═O)R²⁰.

Embodiment 434

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, andC₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁹.

Embodiment 435

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, andbenzyl optionally substituted by 1-3 R¹⁹.

Embodiment 436

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1 R¹⁹, andbenzyl optionally substituted by 1 R¹⁹.

Embodiment 437

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, C₁₋₆alkyl optionally substituted by 1 R¹⁹, andbenzyl.

Embodiment 438

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, methyl optionally substituted by 1 R¹⁹, andbenzyl optionally substituted by 1 R¹⁹.

Embodiment 439

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; andR^(d) is chosen from H, methyl optionally substituted by 1 R¹⁹, andbenzyl.

Embodiment 440

The compound of any of Embodiments 1, 3-156, 200-250, or 300-371,wherein R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areH.

Embodiment 500

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-13 R³⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R³⁹, C₂₋₆alkynyl optionally substituted by 1-9 R³⁹, C₆₋₁₁aryloptionally substituted by 1-11 R³⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R³⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R³⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R³⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R³⁹, 5-15membered heteroaryl optionally substituted by 1-15 R³⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R³⁹, halogen, —CN,—C(═O)R³⁰, —C(═O)OR³⁰, —C(═O)NR³²R³³, —C(═O)C(═O)R³⁰, —C(═NR³⁵)R³⁰,—C(═NR³⁵)NR³²R³³, —C(═NOH)NR³²R³³, —C(═NOR³⁶)R³⁰, —C(═NNR³²R³³)R³⁰,—C(═NNR³⁴C(═O)R³¹)R³⁰, —C(═NNR³⁴C(═O)OR³¹)R³⁰, —C(═S)NR³²R³³, —NC, —NO₂,—NR³²R³³, NR³⁴NR³²R³³, —N═NR³⁴, ═NR³⁰, ═NOR³⁰, —NR³⁴OR³⁶, —NR³⁴C(═O)R³⁰,NR³⁴C(═O)C(═O)R³⁰, —NR³⁴C(═O)OR³¹, —NR³⁴C(═O)C(═O)OR³¹,NR³⁴C(═O)NR³²R³³, —NR³⁴C(═O)NR³⁴C(═O)R³⁰, NR³⁴C(═O)NR³⁴C(═O)OR³⁰,NR³⁴C(═NR³⁵)NR³²R³³, —NR³⁴C(═O)C(═O)NR³²R³³, —NR³⁴C(═S)R³⁰,—NR³⁴C(═S)OR³⁰, NR³⁴C(═S)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³,—NR³⁴P(═O)R⁷⁸R⁷⁸, —NR³⁴P(═O)(NR³²R³³(NR³²R³³), —NR³⁴P(═O)(OR³⁰)(OR³⁰),—NR³⁴P(═O)(SR³⁰)(SR³), —OR³⁰, ═O, —OCN, —OC(═O)R³⁰, —OC(═O)NR³²R³³,—OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³, —OS(═O)R³⁰, —OS(═O)₂R³⁰, —OS(═O)₂OR³⁰,—OS(═O)₂NR³²R³³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR³²R³³(NR³²R³³), —OP(═O)(OR³⁰),—OP(═O)(SR³⁰)(SR³⁰), —Si(R³⁴)₃, —SCN, ═S, —S(═O)_(n)R³⁰, —S(═O)₂OR³⁰,—SO₃R³⁷, —S(═O)₂NR³²R³³, —S(═O)NR³²R³³, —SP(═O)R⁷⁸R⁷⁸,—SP(═O)(NR³²R³³)(NR³²R³³), —SP(═O)(OR³⁰)(OR³⁰), —SP(═O)(SR³⁰)(SR³⁰),—P(═O)R⁷⁸R⁷⁸, —P(═O)(NR³²R³³)(NRR³²R), —P(═O)(OR³⁰)(OR³⁰), and—P(═O)(SR³⁰)(SR³⁰).

Embodiment 501

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-6 R³⁹, C₂₋₆alkenyl optionally substituted by1-6 R³⁹, C₂₋₆alkynyl optionally substituted by 1-6 R³⁹, C₆₋₁₁aryloptionally substituted by 1-6 R³⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R³⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R³⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R³⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-6 R³⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R³⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R³⁹, halogen, —CN,—C(═O)R³⁰, —C(═)OR³⁰, —C(═O)NR³²R³³, —C(═O)C(═O)R³⁰, —C(═NR³⁵)R³⁰,—C(═NR³⁵)NR³²R³³, —C(═NOH)NR³²R³³, —C(═NOR³⁶)R³, —C(═NNR³²R³³)R³⁰,—C(═NNR³⁴C(═O)R³¹)R³⁰, —C(═NNR³⁴C(═O)OR³¹)R³⁰, —C(═S)NR³²R³³, —NC, —NO₂,—NR³²R³³, —NR³⁴NR³²R³³, N═NR³⁴, ═NR³⁰, ═NOR³⁰, —NR³⁴OR³⁶, —NR³⁴C(═O)R³⁰,NR³⁴C(═O)C(═O)R³, —NR³⁴C(═O)OR³¹, —NR³⁴C(═O)C(═O)OR³¹,—NR³⁴C(═O)NR³²R³³, —NR³⁴C(═O)NR³⁴C(═O)R³⁰, —NR³⁴C(═O)NR³⁴C(═O)OR³⁰,—NR³⁴C(═NR³⁵)NR³²R³³, —NR³⁴C(═O)C(═O)NR³²R³⁰,—NR³⁴C(═S)R³⁰,—NR³⁴C(═S)OR³⁰, —NR³⁴C(═S)NR³²R³³, NR³⁴S(═O)₂R³¹,—NR³⁴S(═O)₂NR³²R³³, —NR³⁴P(═O)R⁷⁸R⁷⁸, —NR³⁴P(═O)(NR³²R³³)(NR³²R³³),—NR³⁴P(═O)(OR³⁰)(OR³⁰), —NR³⁴P(═O)(SR³⁰)(SR³), —OR³⁰, ═O, —OCN,—OC(═O)R³, —OC(═O)NR³²R³³, —OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³, —OS(═O)R³⁰,—OS(═O)₂R³⁰, —OS(═O)₂OR³⁰, —OS(═O)₂NR³²R³³, —OP(═O)R⁷⁸R⁷⁸,—OP(═O)(NR³²R³³)(NR³²R³³), —OP(═O)(OR³⁰)(OR³⁰), —OP(═O)(SR³⁰)(SR³⁰),—Si(R³⁴)₃, —SCN, ═S, —S(═O)_(n)R³⁰, —S(═O)₂OR³⁰, —SO₃R³⁷,—S(═O)₂NR³²R³³, —S(═O)NR³²R³³, —SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR³²R³³)(NR³²R³³),—SP(═O)(OR³⁰)(OR³⁰), —SP(═O)(SR³⁰)(SR³⁰), —P(═O)R⁷⁸R⁷⁸,—P(═O)(NR³²R³³)(NR³²R³³), —P(═O)(OR³⁰)(OR³⁰), and—P(═O)(SR³⁰)(SR³⁰)(SR).

Embodiment 502

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-6 R³⁹, C₂₋₆alkenyl optionally substituted by1-6 R³⁹, C₂₋₆alkynyl optionally substituted by 1-6 R³⁹, C₆₋₁₁aryloptionally substituted by 1-6 R³⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R³⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R³⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R³⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-6 R³⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R³⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R³⁹, halogen, —CN,—C(═O)R³⁰, —C(═)OR³⁰, C(═O)NR³²R³³, —C(═)C(═)R³⁰, —NC, —NO₂, —NR³²R³³,—NR³⁴NR³²R³³, —NR³⁴OR³⁶, —NR³⁴C(═O)R³⁰, NR³⁴C(═O)C(═O)R³⁰,—NR³⁴C(═O)OR³¹, —NR³⁴C(═O)C(═O)OR³¹, —NR³⁴C(═O)NR³²R³³,—NR³⁴C(═O)NR³⁴C(═O)R³⁰, —NR³⁴C(═O)NR³⁴C(═O)OR³⁰, —NR³⁴C(═NR³⁵)NR³²R³³,—NR³⁴C(═O)C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O,—OCN, —OC(═O)R³⁰, —OC(═O)NR³²R³³, —OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³,—Si(R³⁴)₃, —SCN, ═S, —S(═O)_(n)R³⁰, —S(═O)₂OR³⁰, —SO₃R³⁷,—S(═O)₂NR³²R³³, —S(═O)NR³²R³³, —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR³²R³³)(NR³²R³³),—P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰).

Embodiment 503

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkenyl optionally substituted by1-3 R³⁹, C₂₋₆alkynyl optionally substituted by 1-3 R³⁹, C₆₋₁₁aryloptionally substituted by 1-3 R³⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-3 R³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R³⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-3 R³⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-3 R³⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R³⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R³⁹, halogen, —CN,—C(═O)R³⁰, —C(═)OR³⁰, —C(═O)NR³²R³³, —C(═O)C(═O)R³⁰, —NC, —NO₂,—NR³²R³³, —NR³⁴NR³²R³³, —NR³⁴OR³⁶, —NR³⁴C(═O)R³⁰, NR³⁴C(═O)C(═O)R³⁰,—NR³⁴C(═O)OR³¹, —NR³⁴C(═O)C(═O)OR³¹, —NR³⁴C(═O)NR³²R³³,—NR³⁴C(═O)NR³⁴C(═O)R³⁰, —NR³⁴C(═O)NR³⁴C(═O)OR³, —NR³⁴C(═NR³⁵)NR³²R³³,—NR³⁴C(═O)C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O,—OCN, —OC(═O)R³⁰, —OC(═O)NR³²R³³, —OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³,—Si(R³⁴)₃, —SCN, ═S, —S(═O)_(n)R³⁰, —S(═O)₂OR³⁰, —SO₃R³⁷,—S(═O)₂NR³²R³³, —S(═O)NR³²R³³, —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR³²R³³(NR³²R³³),—P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰).

Embodiment 504

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkenyl optionally substituted by1-3 R³⁹, C₂₋₆alkynyl optionally substituted by 1-3 R³⁹, C₆₋₁₀aryloptionally substituted by 1-3 R³⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R³⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R³⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R³⁹, 5-10membered heteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN,—C(═O)R³⁰, —C(═)OR³⁰, —C(═O)NR³²R³³, —C(═O)C(═O)R³⁰, —NC, —NO₂,—NR³²R³³, —NR³⁴NR³²R³³, —NR³⁴OR³⁶, —NR³⁴C(═O)R³⁰, —NR³⁴C(═O)C(═O)R³⁰,—NR³⁴C(═O)OR³¹, —NR³⁴═O)C(═O)OR³¹, —NR³⁴C(═O)NR³²R³³,—NR³⁴C(═O)NR³⁴C(═O)R³⁰, NR³⁴C(═O)NR³⁴C(═O)OR³⁰, NR³⁴C(═NR³⁵)NR³²R³³,—NR³⁴C(═O)C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O,—OCN, —OC(═O)R³⁰, —OC(═O)NR³²R³³, —OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³,—Si(R³⁴)₃, —SCN, ═S, —S(═O)_(n)R³⁰, —S(═O)₂OR³⁰, —SO₃R³⁷,—S(═O)₂NR³²R³³, —S(═O)NR³²R³³, —P(═O)R⁷R⁷⁸, —P(═O)(NR³²R³³)(NR³²R³³),—P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰).

Embodiment 505

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkenyl optionally substituted by1-3 R³⁹, C₂₋₆alkynyl optionally substituted by 1-3 R³⁹, C₆₋₁₀aryloptionally substituted by 1-3 R³⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R³⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R³⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R³⁹, 5-10membered heteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN,—C(═O)R³⁰, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,NR³⁴C(═O)OR³¹, —NR³⁴C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³,—OR³⁰, ═O, —OC(═O)R³, —OC(═O)NR³²R³³, —Si(R³⁴)₃, ═S, —S(═O)_(n)R³⁰,—S(═O)₂OR³, —SO₃R³⁷, —S(═O)₂NR³²R³³, —S(═O)NR³²R³³, —P(═O)R⁷⁸R⁷⁸,—P(═O)(NR³²R³³)(NR³²R³³), —P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰).

Embodiment 506

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkenyl optionally substituted by1-3 R³⁹, C₂₋₆alkynyl optionally substituted by 1-3 R³⁹, C₆₋₁₀aryloptionally substituted by 1-3 R³⁹, C₂₋₆arylalkyl optionally substitutedby 1-3 R³⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R³⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R³⁹, 5-10membered heteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN,—C(═O)R³, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,NR³⁴C(═O)OR³¹, —NR³⁴C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³,—OR³⁰, ═O, —OC(═O)R³, OC(═O)NR³²R³³, —Si(R³⁴)₃, ═S, —S(═O)_(n)R³,—S(═O)₂NR³²R³³, and —S(═O)NR³²R³³.

Embodiment 507

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkenyl optionally substituted by1-3 R³⁹, C₂₋₆alkynyl optionally substituted by 1-3 R³⁹, C₆₋₁₀aryloptionally substituted by 1-3 R³⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R³⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R³⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R³⁹, 5-10membered heteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN,—C(═O)R³⁰, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,NR³⁴C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR, ═O,—OC(═O)R³⁰, —OC(═O)NR³²R³³, —Si(R³⁴)₃, ═S, —S(═O)_(n)R³⁰, and—S(═O)₂NR³²R³³.

Embodiment 508

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkenyl optionally substituted by1-3 R³⁹, C₂₋₆alkynyl optionally substituted by 1-3 R³⁹, C₆₋₁₀aryloptionally substituted by 1-3 R³⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R³⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6membered heterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6membered heteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN,—C(═O)R³, —C(═O)OR³, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,—NR³⁴C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O,—OC(═O)R³⁰, —OC(═O)NR³²R³³, —Si(R³⁴)₃, ═S, —S(═O)_(n)R³⁰, and—S(═O)₂NR³²R³³.

Embodiment 509

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₆₋₁₀aryl optionally substituted by1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,—NR³⁴S(═O)₂R³¹, —OR³⁰, ═O, —OC(═O)R³⁰, —OC(═O)NR³²R³³, —Si(R³⁴)₃,—S(═O)_(n)R³⁰, and —S(═O)₂NR³²R³³.

Embodiment 510

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₆₋₁₀aryl optionally substituted by1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰,—C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, —NR³⁴S(═O)₂R³¹, —OR³⁰, ═O,—S(═O)_(n)R³⁰, and —S(═O)₂NR³²R³³.

Embodiment 511

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₆₋₁₀aryl optionally substituted by1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰,—C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, —OR³⁰, and ═O.

Embodiment 512

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl,C₆-10aryl, C₇₋₁₁arylalkyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R³⁰,—C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, —OR³⁰, and ═O.

Embodiment 513

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl,C₆-10aryl, C₇₋₁₁arylalkyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —C(═O)R³⁰,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, and OR³⁰

Embodiment 514

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-13 R³⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R³⁹, C₂₋₆alkynyl optionally substituted by 1-9 R³⁹, C₆₋₁₁aryloptionally substituted by 1-11 R³⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R³⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R³⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R³⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R³⁹, 5-15membered heteroaryl optionally substituted by 1-15 R³⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R³⁹, halogen, —CN,—C(═O)NR³²R³³, —NO₂, —NR³²R³³, and —OR³⁰

Embodiment 515

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-13 R³⁹.

Embodiment 516

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₆₋₁₀aryl optionally substituted by1-3 R³⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —C(═O)OR³⁰,—NR³²R³³, and —OR³⁰.

Embodiment 517

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, phenyl optionally substituted by 1-3R³⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —C(═O)OR³⁰,—NR³²R³³, and —OR³.

Embodiment 518

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl,phenyl optionally substituted by 1-3 R³⁹, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl, halogen, —C(═O)OR³⁰, —NR³²R³³, and —OR³⁰.

Embodiment 519

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl,phenyl optionally substituted by 1 R³⁹, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl optionally substituted by 1 R³⁹, 5-6 memberedheteroaryl, halogen, —C(═O)OR³⁰, —NR³²R³³, and —OR³⁰.

Embodiment 520

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl,phenyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 memberedheteroaryl, halogen, —C(═O)OR³⁰, —NR³²R³³, and —OR

Embodiment 521

The compound of any of Embodiments 1-156, 200-250, 300-371,

or 400-440, wherein R¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R³⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,—NR³⁴C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O,—OC(═O)R³, —OC(═O)NR³²R³³, —Si(R³⁴)₃, ═S, —S(═O)_(n)R³⁰, and—S(═O)₂NR³²R³³.

Embodiment 522

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl optionally substituted by1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)OR³⁰,—C(═O)NR³²R³³, —NR³²R³³, NR³⁴C(═O)R³⁰, —NR³⁴S(═O)₂R³¹, —OR³⁰, ═O,—OC(═O)R³, —S(═O)_(n)R³⁰, and —S(═O)₂NR³²R³³.

Embodiment 523

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl optionally substituted by1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R³⁹, —CN, —C(═O)OR³⁰,—C(═O)NR³²R³³, —NR³²R³³, —NR³⁴S(═O)₂R³¹, —OR³⁰, and ═O.

Embodiment 524

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl optionally substituted by1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R³⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R³⁹, —CN, —C(═O)OR³⁰,—C(═O)NR³²R³³, —NR³²R³³, —NR³⁴S(═O)₂R³¹, and —OR³⁰.

Embodiment 525

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl optionally substituted by1-3 R³⁹, benzyl optionally substituted by 1-3 R³⁹, cyclopropyloptionally substituted by 1-3 R³⁹, 6 membered heterocycloalkyloptionally substituted by 1-3 R³⁹, 5 membered heteroaryl optionallysubstituted by 1-3 R³⁹, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³,—NR³⁴S(═O)₂R³¹, —OR³⁰, and ═O.

Embodiment 526

The compound of any of Embodiments 1-156, 200-250, 300-371,

or 400-440, wherein R¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R³⁹, benzyl optionally substituted by 1-3 R³⁹,cyclopropyl optionally substituted by 1-3 R³⁹, 6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5 memberedheteroaryl optionally substituted by 1-3 R³⁹, —CN, —C(═O)OR³⁰,—C(═O)NR³²R³³, —NR³²R³³, —NR³⁴S(═O)₂R³¹, and —OR³⁰.

Embodiment 527

The compound of any of Embodiments 1-156, 200-250, 300-371,

or 400-440, wherein R¹⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R³⁹, C₂₋₆alkynyl optionallysubstituted by 1-3 R³⁹, benzyl optionally substituted by 1-3 R³⁹,cyclopropyl optionally substituted by 1-3 R³⁹, morpholinyl optionallysubstituted by 1-3 R³⁹, pyrazolyl optionally substituted by 1-3 R³⁹,—CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, —NR³⁴S(═O)₂R³¹, —OR³⁰, and ═O.

Embodiment 528

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl optionally substituted by1-3 R³⁹, benzyl optionally substituted by 1-3 R³⁹, cyclopropyloptionally substituted by 1-3 R³⁹, morpholinyl optionally substituted by1-3 R³⁹, pyrazolyl optionally substituted by 1-3 R³⁹, —CN, —C(═O)OR³⁰,—C(═O)NR³R³³, —NR³²R³³, NR³⁴S(═O)₂R³¹, and —OR³⁰.

Embodiment 529

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl, C₇₋₁₁arylalkyloptionally substituted by 1-3 R³⁹, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, —CN, —C(═O)OR³⁰,—C(═O)NR³²R³³, —NR³²R³³, —NR³⁴S(═O)₂R³¹, —OR³⁰, and ═O.

Embodiment 530

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl, C₇₋₁₁arylalkyloptionally substituted by 1-3 R³⁹, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, —CN, —C(═O)OR³⁰,—C(═O)NR³²R³³, —NR³²R³³, —NR³⁴S(═O)₂R³¹, and —OR³⁰

Embodiment 531

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl, benzyl optionallysubstituted by 1-3 R³⁹, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,5-6 membered heteroaryl, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³,—NR³⁴S(═O)₂R³¹, —OR³⁰, and ═O.

Embodiment 532

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl, benzyl optionallysubstituted by 1-3 R³⁹, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,5-6 membered heteroaryl, —CN, —C(═0O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³,—NR³⁴S(═O)₂R³¹, and —OR³⁰

Embodiment 533

The compound of any of Embodiments 1-156, 200-250, 300-371, or 400-440,wherein R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl, benzyl optionallysubstituted by 1-3 R³⁹, cyclopropyl, morpholinyl, pyrazolyl, —CN,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, —NR³⁴S(═O)₂R³¹, —OR³⁰, and ═O.

Embodiment 600

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-6 R⁴⁹, C₂₋₆alkenyl optionally substituted by1-6 R⁴⁹, C₂₋₆alkynyl optionally substituted by 1-6 R⁴⁹, C₆₋₁₁aryloptionally substituted by 1-6 R⁴⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R⁴⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R⁴⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R⁴⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R⁴⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-6 R⁴⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R⁴⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R⁴⁹.

Embodiment 601

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-6 R⁴⁹, C₂₋₆alkenyl optionally substituted by1-6 R⁴⁹, C₂₋₆alkynyl optionally substituted by 1-6 R⁴⁹, C₆₋₁₀aryloptionally substituted by 1-6 R⁴⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-6 R⁴⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁴⁹, 3-10membered heterocycloalkyl optionally substituted by 1-6 R⁴⁹, and 5-10membered heteroaryl optionally substituted by 1-6 R⁴⁹.

Embodiment 602

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, C₂₋₆alkenyl optionally substituted by1-3 R⁴⁹, C₂₋₆alkynyl optionally substituted by 1-3 R⁴⁹, C₆₋₁₀aryloptionally substituted by 1-3 R⁴⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R⁴⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-10membered heteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 603

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁴⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁴⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 604

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁴⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁴⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 605

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, phenyl optionally substituted by 1-3R⁴⁹, benzyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-3 R⁴⁹, 3-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 606

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, phenyl optionally substituted by 1-3R⁴⁹, benzyl optionally substituted by 1-3 R⁴⁹, and C₃₋₆cycloalkyloptionally substituted by 1-3 R⁴⁹.

Embodiment 607

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹, phenyl optionallysubstituted by 1-3 R⁴⁹, benzyl optionally substituted by 1-3 R⁴⁹,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 608

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹, phenyl optionallysubstituted by 1-3 R⁴⁹, benzyl optionally substituted by 1-3 R⁴⁹, andC₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶,R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl.

Embodiment 609

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹, phenyl optionallysubstituted by 1-3 R⁴⁹, benzyl optionally substituted by 1-3 R⁴⁹,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is H.

Embodiment 610

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyloptionally substituted by 1-6 R⁴⁹.

Embodiment 611

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 612

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 613

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₆₋₁₀aryloptionally substituted by 1-3 R⁴⁹, benzyl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 614

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, phenyl optionally substituted by 1-3R⁴⁹, benzyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 615

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, phenyl optionally substituted by 1-3R⁴⁹, benzyl optionally substituted by 1-3 R⁴⁹, and cyclopropyloptionally substituted by 1-3 R⁴⁹.

Embodiment 616

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R, R³⁵, R³⁶ andR³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, phenyl optionally substituted by 1-3R⁴⁹, benzyl optionally substituted by 1-3 R⁴⁹, cyclopropyl, thienyl, andpyrazinyl.

Embodiment 617

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R², R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R, R³¹, R, R³⁵, R³⁶ andR³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyl,phenyl, benzyl optionally substituted by 1-3 R⁴⁹, cyclopropyl, thienyl,and pyrazinyl.

Embodiment 618

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyl,phenyl optionally substituted by 1-3 R⁴⁹, cyclopropyl, 5 memberedheterocycloalkyl, and 5 membered heteroaryl.

Embodiment 619

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, phenyloptionally substituted by 1-3 R⁴⁹, cyclopropyl, 5 memberedheterocycloalkyl, and 5 membered heteroaryl.

Embodiment 620

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyl,phenyl optionally substituted by 1 R⁴⁹, C₃₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 621

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, phenyloptionally substituted by 1 R⁴⁹, C₃₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 622

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyl,phenyl, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl.

Embodiment 623

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, phenyl,C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl.

Embodiment 624

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R², R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, C₁₋₆alkyl,phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5 memberedheteroaryl.

Embodiment 625

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H, phenyl,cyclopropyl, 5 membered heterocycloalkyl, and 5 membered heteroaryl.

Embodiment 626

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3R⁴⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R⁴⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴,R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R⁴⁹.

Embodiment 627

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₆-10aryl optionally substituted by 1-3 R⁴⁹, benzyl optionallysubstituted by 1-3 R⁴⁹, cyclopropyl optionally substituted by 1-3 R⁴⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴,R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R⁴⁹.

Embodiment 628

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹, phenyl optionallysubstituted by 1-3 R⁴⁹, benzyl optionally substituted by 1-3 R⁴⁹,cyclopropyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 629

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-3 R⁴⁹, 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹.

Embodiment 630

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl, 5-6membered heterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R⁴⁹.

Embodiment 631

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 632

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl optionally substituted by 1-3 R⁴⁹, cyclopropyl, 5membered heterocycloalkyl, and 5 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R⁴⁹.

Embodiment 633

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionally substitutedby 1-3 R⁴⁹, and cyclopropyl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴,R³⁵, R³⁶ and R³⁷ at each occurrence is independently chosen from H andC₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 634

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl optionally substituted by 1 R⁴⁹, C₃₋₆cycloalkyl, 5-6membered heterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R⁴⁹.

Embodiment 635

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1 R⁴⁹, C₃₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 636

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵,R³⁶ and R³⁷ at each occurrence is independently chosen from H andC₁₋₆alkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 637

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 638

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹.

Embodiment 639

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 640

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3R⁴⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R⁴⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴,R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl.

Embodiment 641

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₆-10aryl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-3 R⁴⁹, 3-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 642

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹, phenyl optionallysubstituted by 1-3 R⁴⁹, benzyl optionally substituted by 1-3 R⁴⁹, andC₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶,R²⁷, R³, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl.

Embodiment 643

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-3 R⁴⁹, 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 644

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionallysubstituted by 1-3 R⁴⁹, and C₃₋₆cycloalkyl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³,R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independently chosenfrom H and C₁₋₆alkyl.

Embodiment 645

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl.

Embodiment 646

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl optionally substituted by 1-3 R⁴⁹, cyclopropyl, 5membered heterocycloalkyl, and 5 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl.

Embodiment 647

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionally substitutedby 1-3 R⁴⁹, C₃₋₆cycloalkyl, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 648

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl optionally substituted by 1-3 R⁴⁹,C₃₋₆cycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl.

Embodiment 649

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl optionally substituted by 1-3 R⁴⁹,cyclopropyl, thienyl, and pyrazinyl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹,R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independently chosen from Hand C₁₋₆alkyl.

Embodiment 650

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵,R³⁶ and R³⁷ at each occurrence is independently chosen from H andC₁₋₆alkyl.

Embodiment 651

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 652

The compound of any of Embodiments 1-156, 200-250, 300-371,

400-440, or 500-533, wherein R²⁰ at each occurrence is independentlychosen from H, C₁₋₆alkyl, phenyl, cyclopropyl, 5 memberedheterocycloalkyl, and 5 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷,R³, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl.

Embodiment 653

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 654

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3R⁴⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R⁴⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴,R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 655

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₆-10aryl optionally substituted by 1-3 R⁴⁹, benzyl optionallysubstituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3R⁴⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R⁴⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴,R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 656

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionally substitutedby 1-3 R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6membered heteroaryl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 657

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionally substitutedby 1-3 R⁴⁹, C₃₋₆cycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³, R³¹, R³⁴, R³, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 658

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl, benzyl optionally substituted by 1-3 R⁴⁹, C₃₋₆cycloalkyl, and5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵,R³⁶ and R³⁷ at each occurrence is H.

Embodiment 659

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionally substitutedby 1-3 R⁴⁹, cyclopropyl optionally substituted by 1-3 R⁴⁹; R²¹, R²⁴,R²⁵, R²⁶, R²⁷, R³, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 660

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1-3 R⁴⁹, benzyl optionally substitutedby 1-3 R⁴⁹, and cyclopropyl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴,R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 661

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl, benzyl optionally substituted by 1-3 R⁴⁹, cyclopropyl, thienyl,and pyrazinyl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷at each occurrence is H.

Embodiment 662

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl optionally substituted by 1 R⁴⁹, C₃₋₆cycloalkyl, 5-6membered heterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 663

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl optionally substituted by 1 R⁴⁹, C₃₋₆cycloalkyl, and 5-6 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is H.

Embodiment 664

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵,R³⁶ and R³⁷ at each occurrence is H.

Embodiment 665

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl, C₃₋₆cycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶,R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.

Embodiment 666

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5membered heteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is H.

Embodiment 667

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰ at each occurrence is independently chosen from H,phenyl, cyclopropyl, 5 membered heterocycloalkyl, and 5 memberedheteroaryl; R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ ateach occurrence is H.

Embodiment 668

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440, or500-533, wherein R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶and R³⁷ at each occurrence is H.

Embodiment 700

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-13 R⁴⁹, C₂₋₆alkenyloptionally substituted by 1-11 R⁴⁹, C₂₋₆alkynyl optionally substitutedby 1-9 R⁴⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁴⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R⁴⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R⁴⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by1-32 R⁴⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28R⁴⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40R⁴⁹, 5-15 membered heteroaryl optionally substituted by 1-15 R⁴⁹, and6-21 membered heteroarylalkyl optionally substituted by 1-27 R⁴⁹.

Embodiment 701

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹, C₂₋₆alkenyloptionally substituted by 1-3 R⁴⁹, C₂₋₆alkynyl optionally substituted by1-3 R⁴⁹, C₆₋₁₁aryl optionally substituted by 1-3 R⁴⁹, C₇₋₁₆arylalkyloptionally substituted by 1-3 R⁴⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-3 R⁴⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by1-3 R⁴⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-3R⁴⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-3R⁴⁹, 5-15 membered heteroaryl optionally substituted by 1-3 R⁴⁹, and6-21 membered heteroarylalkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 702

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹, C₂₋₆alkenyloptionally substituted by 1-3 R⁴⁹, C₂₋₆alkynyl optionally substituted by1-3 R⁴⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁴⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R⁴⁹, C₃₋₁₀cycloalkyl optionallysubstituted by 1-3 R⁴⁹, 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R⁴⁹, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁴⁹.

Embodiment 703

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹, C₆₋₁₀aryloptionally substituted by 1-3 R⁴⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R⁴⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-10membered heterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-10membered heteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 704

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹, phenyloptionally substituted by 1-3 R⁴⁹, benzyl optionally substituted by 1-3R⁴⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R⁴⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁴⁹.

Embodiment 705

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹, phenyloptionally substituted by 1-3 R⁴⁹, benzyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 706

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹ and 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 707

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹ and 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁴⁹.

Embodiment 708

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹ and 5-6 memberedheterocycloalkyl.

Embodiment 709

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹ and 5 memberedheterocycloalkyl optionally substituted by 1-6 R⁴⁹.

Embodiment 710

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹ and 5 memberedheterocycloalkyl.

Embodiment 711

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹ andpyrrolidinyl.

Embodiment 712

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R⁴⁹ and 5 memberedheterocycloalkyl.

Embodiment 713

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is C₁₋₆alkyloptionally substituted by 1-6 R⁴⁹.

Embodiment 714

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, or 600-668, wherein R²⁸ at each occurrence is C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹.

Embodiment 750

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁵⁹,C₂₋₆alkynyl optionally substituted by 1-9 R⁵⁹, C₆₋₁₁aryl optionallysubstituted by 1-11 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R⁵⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁵⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁵⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R⁵⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R⁵⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R⁵⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R⁵⁹; or any R²² and R²³and/or R³² and R³³ may form, together with the nitrogen atom to whichthey are attached, a 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R⁶⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R⁶⁹.

Embodiment 751

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹,C₂₋₆alkynyl optionally substituted by 1-3 R⁵⁹, C₆₋₁₁aryl optionallysubstituted by 1-3 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3R⁵⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R⁵⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-3 R⁵⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-3 R⁵⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R⁵⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R⁵⁹; or any R²² and R²³and/or R³² and R³³ may form, together with the nitrogen atom to whichthey are attached, a 3-15 membered heterocycloalkyl optionallysubstituted by 1-3 R⁶⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-3 R⁶⁹.

Embodiment 752

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹,C₂₋₆alkynyl optionally substituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁵⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R⁵⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹; or any R²² and R²³ and/orR³² and R³³ may form, together with the nitrogen atom to which they areattached, a 3-10 membered heterocycloalkyl optionally substituted by 1-3R⁶⁹ or a 5-10 membered heteroaryl optionally substituted by 1-3 R⁶⁹.

Embodiment 753

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹,C₂₋₆alkynyl optionally substituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁵⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R⁵⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹.

Embodiment 754

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁵⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R⁵⁹, and 5-10 membered heteroaryloptionally substituted by 1-3 R⁵⁹.

Embodiment 755

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹.

Embodiment 756

The compound of any of Embodiments 1-156, 200-250, 300-371,

400-440, 500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ ateach occurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹.

Embodiment 757

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁵⁹, 4-5 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-9 memberedheteroaryl optionally substituted by 1-3 R⁵⁹.

Embodiment 758

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₀cycloalkyl, 3-6 membered heterocycloalkyl, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹.

Embodiment 759

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₀cycloalkyl, 4-5 membered heterocycloalkyl, and 5-9 memberedheteroaryl optionally substituted by 1-3 R⁵⁹.

Embodiment 760

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, and5-6 membered heteroaryl optionally substituted by 1-3 R⁵⁹.

Embodiment 761

The compound of any of Embodiments 1-156, 200-250, 300-371,

400-440, 500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ ateach occurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, and 6membered heteroaryl optionally substituted by 1-3 R⁵⁹.

Embodiment 762

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁵⁹, phenyl optionally substituted by 1 R⁵⁹, and 6membered heteroaryl optionally substituted by 1 R⁵⁹.

Embodiment 763

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² and R³² at each occurrence areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁵⁹, C₂₋₆alkynyloptionally substituted by 1-9 R⁵⁹, C₆₋₁₁aryl optionally substituted by1-11 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁵⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁵⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R⁵⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R⁵⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R⁵⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R⁵⁹, and 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R⁵⁹; R²³ and R³³ at each occurrence is independentlychosen from H and C₁₋₆alkyl; or any R²² and R²³ and/or R³² and R³³ mayform, together with the nitrogen atom to which they are attached, a 3-15membered heterocycloalkyl optionally substituted by 1-28 R⁶⁹ or a 5-15membered heteroaryl optionally substituted by 1-15 R⁶⁹.

Embodiment 764

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² and R³² at each occurrence areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁵⁹, C₆₋₁₁aryl optionally substituted by1-3 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R⁵⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-3 R⁵⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R⁵⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-3 R⁵⁹, 5-15 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹, and 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R⁵⁹; R²³ and R³³ at each occurrence is independentlychosen from H and C₁₋₆alkyl; or any R²² and R²³ and/or R³² and R³³ mayform, together with the nitrogen atom to which they are attached, a 3-15membered heterocycloalkyl optionally substituted by 1-3 R⁶⁹ or a 5-15membered heteroaryl optionally substituted by 1-3 R⁶⁹

Embodiment 765

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² and R³² at each occurrence areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁵⁹, bezyl optionallysubstituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R⁵⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R⁵⁹,and 5-10 membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³ andR³³ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 766

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² and R³² at each occurrence areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁵⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R⁵⁹, and 5-10 membered heteroaryloptionally substituted by 1-3 R⁵⁹; R²³ and R³³ at each occurrence areindependently chosen from H and C₁₋₆alkyl.

Embodiment 767

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² and R³² at each occurrence areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, benzyl optionallysubstituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R⁵⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R⁵⁹,and 5-10 membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³ andR³³ at each occurrence are independently chosen from H and C₁₋₆alkyl.

Embodiment 768

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁵⁹, 4-5 membered heterocycloalkyloptionally substituted by 1-3 R⁵⁹, and 5-9 membered heteroaryloptionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrenceis independently chosen from H and C₁₋₆alkyl.

Embodiment 769

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² and R³² at each occurrence areindependently chosen from H, C₁₋₆alkyl, phenyl, benzyl, C₃₋₆cycloalkyl,3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; R²³ and R³³at each occurrence are independently chosen from H and C₁₋₆alkyl.

Embodiment 770

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl, 3-6membered heterocycloalkyl, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence isindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R⁵⁹.

Embodiment 771

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² and R³² at each occurrence areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, benzyl, C₃₋₁₀cycloalkyl,4-5 membered heterocycloalkyl, and 5-9 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹; R²³ and R³³ at each occurrence is independentlychosen from H and C₁₋₆alkyl optionally substituted by 1-3 R⁵⁹.

Embodiment 772

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₆₋₁₀aryl optionally substituted by 1-3R⁵⁹, and 5-10 membered heteroaryl optionally substituted by 1-3 R⁵⁹;R²³, R³² and R³³ at each occurrence is independently chosen from H andC₁₋₆alkyl.

Embodiment 773

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, phenyl optionally substituted by 1-3 R⁵⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³²and R³³ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 774

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² and R³² at each occurrence areindependently chosen from H, phenyl optionally substituted by 1-3 R⁵⁹,benzyl, and 6 membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³and R³³ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 775

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, phenyl optionally substituted by 1 R⁵⁹, and6 membered heteroaryl optionally substituted by 1 R⁵⁹; R²³, R³² and R³³at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 776

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁵⁹, C₂₋₆alkynyloptionally substituted by 1-9 R⁵⁹, C₆₋₁₁aryl optionally substituted by1-11 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁵⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁵⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-32 R⁵⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-28 R⁵⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-40 R⁵⁹, 5-15 membered heteroaryl optionallysubstituted by 1-15 R⁵⁹, and 6-21 membered heteroarylalkyl optionallysubstituted by 1-27 R⁵⁹; R²³, R³² and R³³ at each occurrence is H; orany R²² and R²³ and/or R³² and R³³ may form, together with the nitrogenatom to which they are attached, a 3-15 membered heterocycloalkyloptionally substituted by 1-28 R⁶⁹ or a 5-15 membered heteroaryloptionally substituted by 1-15 R⁶⁹.

Embodiment 777

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁵⁹, C₆₋₁₁aryl optionally substituted by1-3 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-3 R⁵⁹, C₄₋₁₇cycloalkylalkyloptionally substituted by 1-3 R⁵⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-3 R⁵⁹, 4-21 membered heterocycloalkylalkyloptionally substituted by 1-3 R⁵⁹, 5-15 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹, and 6-21 membered heteroarylalkyl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence is H; or anyR²² and R²³ and/or R³² and R³³ may form, together with the nitrogen atomto which they are attached, a 3-15 membered heterocycloalkyl optionallysubstituted by 1-3 R⁶⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-3 R⁶⁹.

Embodiment 778

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁵⁹, C₂₋₆alkynyloptionally substituted by 1-3 R⁵⁹, C₆₋₁₀aryl optionally substituted by1-3 R⁵⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁵⁹,C₃₋₁₀-cycloalkyl optionally substituted by 1-3 R⁵⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³ at eachoccurrence is H; or any R²² and R²³ and/or R³² and R³³ may form,together with the nitrogen atom to which they are attached, a 3-10membered heterocycloalkyl optionally substituted by 1-3 R⁶⁹ or a 5-10membered heteroaryl optionally substituted by 1-3 R⁶⁹.

Embodiment 779

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁵⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R⁵⁹, and 5-10 membered heteroaryloptionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrenceis H.

Embodiment 780

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl, 3-6membered heterocycloalkyl, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence is H; or anyR²² and R²³ and/or R³² and R³³ may form, together with the nitrogen atomto which they are attached, a 3-10 membered heterocycloalkyl optionallysubstituted by 1-3 R⁶⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁶⁹.

Embodiment 781

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl, 3-6membered heterocycloalkyl, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence is H.

Embodiment 782

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl, 4-5membered heterocycloalkyl, and 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence is H.

Embodiment 783

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl, 4-5membered heterocycloalkyl optionally substituted by 1-3 R⁵⁹, and 5-9membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³at each occurrence is H.

Embodiment 784

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R⁵⁹, phenyl optionally substituted by 1-3 R⁵⁹, C₃₋₁₀cycloalkyl, 4-5membered heterocycloalkyl, and 5-9 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrence is H.

Embodiment 785

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, C₆₋₁₀aryl optionally substituted by 1-3R⁵⁹, and 5-10 membered heteroaryl optionally substituted by 1-3 R⁵⁹;R²³, R³² and R³³ at each occurrence is H.

Embodiment 786

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, phenyl optionally substituted by 1-3 R⁵⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³²and R³³ at each occurrence is H.

Embodiment 787

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, phenyl optionally substituted by 1-3 R⁵⁹,and 6 membered heteroaryl optionally substituted by 1-3 R⁵⁹; R²³, R³²and R³³ at each occurrence is H.

Embodiment 788

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²² at each occurrence isindependently chosen from H, phenyl optionally substituted by 1 R⁵⁹, and6 membered heteroaryl optionally substituted by 1 R⁵⁹; R²³, R³² and R³³at each occurrence is H.

Embodiment 789

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 790

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is H.

Embodiment 791

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-13 R⁵⁹; or any R²² and R²³ and/or R³² and R³³ may form,together with the nitrogen atom to which they are attached, a 3-15membered heterocycloalkyl optionally substituted by 1-28 R⁶⁹ or a 5-15membered heteroaryl optionally substituted by 1-15 R⁶⁹.

Embodiment 792

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-6 R⁵⁹; or any R²² and R²³ and/or R³² and R³³ may form,together with the nitrogen atom to which they are attached, a 3-15membered heterocycloalkyl optionally substituted by 1-6 R⁶⁹ or a 5-15membered heteroaryl optionally substituted by 1-6 R⁶⁹.

Embodiment 793

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-6 R⁵⁹; or any R²² and R²³ and/or R³² and R³³ may form,together with the nitrogen atom to which they are attached, a 3-10membered heterocycloalkyl optionally substituted by 1-6 R⁶⁹ or a 5-10membered heteroaryl optionally substituted by 1-6 R⁶⁹.

Embodiment 794

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl optionallysubstituted by 1-6 R⁵⁹; or any R²² and R²³ and/or R³² and R³³ may form,together with the nitrogen atom to which they are attached, a 3-6membered heterocycloalkyl optionally substituted by 1-6 R⁶⁹ or a 5-6membered heteroaryl optionally substituted by 1-6 R⁶⁹.

Embodiment 795

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, or 700-714, wherein R²², R²³, R³² and R³³ at eachoccurrence is independently chosen from H and C₁₋₆alkyl optionally; orany R²² and R²³ and/or R³² and R³³ may form, together with the nitrogenatom to which they are attached, a 3-6 membered heterocycloalkyl or a5-6 membered heteroaryl.

Embodiment 800

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, or 750-795, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-6 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-6 R⁷⁹,C₂₋₆alkynyl optionally substituted by 1-6 R⁷⁹, C₆₋₁₁aryl optionallysubstituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R⁷⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R⁷⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R⁷⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R⁷⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-6 R⁷⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R⁷⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R⁷⁹, halogen, —CN,—C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —(═O)C(═O)R⁷⁰, —C(═NR⁷⁵)R⁷⁰,—C(═NR⁷⁵)NR⁷²R⁷³, —C(═NOH)NR⁷²R⁷³, —C(═NOR⁷⁶)R⁷⁰, —C(═NNR⁷²R⁷³)R⁷⁰,—C(═NNR⁷⁴C(═O)R⁷¹)R⁷⁰, —C(═NNR⁷⁴C(═O)OR⁷¹)R⁷⁰, —C(═S)NR⁷²R⁷³, —NC, —NO₂,—NR⁷²R⁷³, —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, ═NR⁷⁰, ═NOR⁷⁰, —NR⁷⁴OR⁷⁶,—NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)C(═O)OR⁷¹,—NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰,—NR⁷⁴C(═NR⁷⁵)NR⁷²R⁷³, —NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —NR⁷⁴C(═S)R⁷⁰,—NR⁷⁴C(═S)OR⁷⁰, —NR⁷⁴C(═S)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³,—NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —NR⁷⁴P(═)(OR⁷⁰)(OR⁷⁰),—NR⁷⁴P(═O)(SR⁷⁰)(SR⁷⁰), —OR⁷⁰, ═O, —OCN, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³,—OC(═O)OR⁷⁰, —OC(═NR⁷⁵)NR⁷²R⁷³, —OS(═O)R⁷⁰, —OS(═O)₂R⁷⁰, —OS(═O)₂OR⁷⁰,—OS(═O)₂NR⁷²R⁷³, —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),—OP(═O)(OR⁷⁰)(OR⁷⁰), —OP(═O)(SR⁷⁰)(SR⁷⁰), —Si(R⁷⁴)₃, —SCN, ═S,—S(═O)_(n)R⁷⁰, —S(═O)₂OR⁷⁰, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,—SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),—SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),—P(═O)(OR⁷⁰)(OR⁷⁰), and —P(═O)(SR⁷⁰)(SR⁷⁰).

Embodiment 801

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, or 750-795, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-6 R⁷⁹, C₆₋₁₁aryl optionally substituted by 1-6 R⁷⁹,C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-6 R⁷⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R⁷⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰,—C(═O)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³, —NR⁷⁴NR⁷²R⁷³, —NR⁷⁴OR⁷⁶,—NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)NR⁷²R⁷³,—NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³, —OR⁷⁰, ═O,—OCN, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰, Si(R⁷⁴)₃, —SCN, ═S,—S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³.

Embodiment 802

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, or 750-795, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-6 R⁷⁹, C₆10aryl optionally substituted by 1-6 R⁷⁹,C₇₋₁₁arylalkyl optionally substituted by 1-6 R⁷⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-6 R⁷⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-6 R⁷⁹, 5-10 membered heteroaryl optionallysubstituted by 1-6 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰,—C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹,—NR⁷⁴C(═O)NR⁷²R⁷³, NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴S(═O)₂R⁷¹,—NR⁷⁴S(═O)₂NR⁷²R⁷³, —OR⁷⁰, ═O, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰,—Si(R⁷⁴)₃, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³.

Embodiment 803

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, or 750-795, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁷⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁷⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁷⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R⁷⁹, 5-10 membered heteroaryl optionallysubstituted by 1-3 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰, —C(═0O)OR⁷⁰,—C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹,NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴S(═O)₂R⁷¹,—NR⁷⁴S(═O)₂NR⁷²R⁷³, —OR⁷⁰, ═O, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰,—Si(R⁷⁴)₃, —S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³.

Embodiment 804

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, or 750-795, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, phenyl optionally substituted by 1-3 R⁷⁹, benzyloptionally substituted by 1-3 R⁷⁹, C₃₋₆cycloalkyl optionally substitutedby 1-3 R⁷⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3R⁷⁹, 5-6 membered heteroaryl optionally substituted by 1-3 R⁷⁹, halogen,—CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³,—NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴C(═)OR⁷¹, NR⁷⁴C(═O)NR⁷²R⁷³, NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰,—NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³, —OR⁷⁰, ═O, —OC(═O)R⁷⁰,—OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰, —Si(R⁷⁴)₃, —S(═O)_(n)R⁷⁰, and—S(═O)₂NR⁷²R⁷³.

Embodiment 805

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, or 750-795, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, phenyl optionally substituted by 1-3 R⁷⁹, benzyloptionally substituted by 1-3 R⁷⁹, C₃₋₆cycloalkyl optionally substitutedby 1-3 R⁷⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3R⁷⁹, 5-6 membered heteroaryl optionally substituted by 1-3 R⁷⁹, halogen,—CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³,—NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³,—S(═O)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³.

Embodiment 806

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, or 750-795, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, phenyl optionally substituted by 1-3 R⁷⁹, benzyloptionally substituted by 1-3 R⁷⁹, C₃₋₆cycloalkyl optionally substitutedby 1-3 R⁷⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3R⁷⁹, 5-6 membered heteroaryl optionally substituted by 1-3 R⁷⁹, halogen,—CN, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, —OR⁷⁰, and —S(═O)_(n)R⁷⁰.

Embodiment 807

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, or 750-795, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, phenyl optionally substituted by 1-3 R⁷⁹, benzyloptionally substituted by 1-3 R⁷⁹, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)NR⁷²R⁷³,—NR⁷²R⁷³, —OR⁷⁰, and —S(═O)_(n)R⁷⁰.

Embodiment 808

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, or 750-795, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹, phenyl optionally substituted by 1-3 R⁷⁹, benzyloptionally substituted by 1-3 R⁷⁹, cyclopropyl, 5-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)NR⁷²R⁷³,—NR⁷²R⁷³, —OR⁷⁰, and —S(═O)_(n)R⁷⁰

Embodiment 809

The compound of any of Embodiments 800-808, wherein R³⁹ at eachoccurrence is independently chosen from C₁₋₆alkyl optionally substitutedby 1-3 R⁷⁹, benzyl optionally substituted by 1-3 R⁷⁹, and 5-6 memberedheteroaryl.

Embodiment 810

The compound of any of Embodiments 800-808, wherein R³⁹ at eachoccurrence is independently chosen from C₁₋₆alkyl optionally substitutedby 1-3 R⁷⁹, benzyl optionally substituted by 1-3 R⁷⁹, and 6 memberedheteroaryl.

Embodiment 811

The compound of any of Embodiments 800-810, wherein R⁴⁹ at eachoccurrence is independently chosen from C₁₋₆alkyl optionally substitutedby 1-3 R⁷⁹, phenyl optionally substituted by 1-3 R⁷⁹, 5-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —C(═O)NR⁷²R⁷³, and—NR⁷²R⁷³.

Embodiment 812

The compound of any of Embodiments 800-810, wherein R⁴⁹ at eachoccurrence is independently chosen from C₁₋₆alkyl optionally substitutedby 1-3 R⁷⁹, phenyl optionally substituted by 1-3 R⁷⁹, 5-6 memberedheterocycloalkyl, 6 membered heteroaryl, halogen, —C(═O)NR⁷²R⁷³, and—NR⁷²R⁷³.

Embodiment 813

The compound of any of Embodiments 800-812, wherein R⁵⁹ at eachoccurrence is independently chosen from C₁₋₆alkyl optionally substitutedby 1-3 R⁷⁹, phenyl optionally substituted by 1-3 R⁷⁹, cyclopropyl, 5-6membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN,—NR⁷²R⁷³, —OR⁷⁰, and —S(═O)R⁷⁰.

Embodiment 814

The compound of any of Embodiments 800-812, wherein R⁵⁹ at eachoccurrence is independently chosen from C₁₋₆alkyl optionally substitutedby 1-3 R⁷⁹, phenyl optionally substituted by 1-3 R⁷⁹, cyclopropyl, 6membered heterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN,—NR⁷²R⁷³, —OR⁷⁰, and —S(═O)_(n)R⁷⁰

Embodiment 815

The compound of any of Embodiments 800-814, wherein R⁶⁹ at eachoccurrence is independently chosen from C₁₋₆alkyl optionally substitutedby 1-3 R⁷⁹.

Embodiment 816

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, or 750-795, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁷⁹.

Embodiment 817

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, or 750-795, wherein R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ ateach occurrence is independently C₁₋₆alkyl.

Embodiment 850

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R⁸⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R⁸⁹, C₂₋₆alkynyl optionally substituted by 1-9 R⁸⁹,C₆₋₁₁aryl optionally substituted by 1-11 R⁸⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R⁸⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R⁸⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁸⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R⁸⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R⁸⁹, 5-15membered heteroaryl optionally substituted by 1-15 R⁸⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R⁸⁹.

Embodiment 851

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R⁸⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R⁸⁹, C₂₋₆alkynyl optionally substituted by 1-6 R⁸⁹,C₆₋₁₀aryl optionally substituted by 1-6 R⁸⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-6 R⁸⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6R⁸⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R⁸⁹,and 5-10 membered heteroaryl optionally substituted by 1-6 R⁸⁹.

Embodiment 852

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁸⁹, C₂₋₆alkenyl optionallysubstituted by 1-3 R⁸⁹, C₂₋₆alkynyl optionally substituted by 1-3 R⁸⁹,C₆₋₁₀aryl optionally substituted by 1-3 R⁸⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-3 R⁸⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R⁸⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R⁸⁹,and 5-10 membered heteroaryl optionally substituted by 1-3 R⁸⁹.

Embodiment 853

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁸⁹, phenyl optionallysubstituted by 1-3 R⁸⁹, benzyl optionally substituted by 1-3 R⁸⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁸⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁸⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁸⁹.

Embodiment 854

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₃₋₁₀cycloalkyl, 3-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 855

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁸⁹, phenyl optionallysubstituted by 1-3 R⁸⁹, benzyl optionally substituted by 1-3 R⁸⁹,C₅₋₆cycloalkyl optionally substituted by 1-3 R⁸⁹, 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁸⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁸⁹.

Embodiment 856

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 857

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, C₅₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and5-6 membered heteroaryl.

Embodiment 858

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 membered heterocycloalkyloptionally substituted by 1 R⁸⁹, and 5-6 membered heteroaryl.

Embodiment 859

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H andC₁₋₆alkyl optionally substituted by 1-3 R⁸⁹.

Embodiment 860

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independently chosen from H andC₁₋₆alkyl.

Embodiment 861

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, or 800-817, wherein R⁷⁰, R⁷¹, R⁷⁴,R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is H.

Embodiment 862

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-13 R⁹⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R⁹⁹, C₂₋₆alkynyl optionally substituted by 1-9 R⁹⁹, C₆₋₁₁aryloptionally substituted by 1-11 R⁹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R⁹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R⁹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R⁹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R⁹⁹, 5-15membered heteroaryl optionally substituted by 1-15 R⁹⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R⁹⁹; or any R⁷²and R⁷³ may form, together with the nitrogen atom to which they areattached, a 3-15 membered heterocycloalkyl optionally substituted by1-28 R¹⁰⁹ or a 5-15 membered heteroaryl optionally substituted by 1-15R¹⁰⁹.

Embodiment 863

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-6 R⁹⁹, C₂₋₆alkenyl optionally substituted by1-6 R⁹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R⁹⁹, C₆₋₁₁aryloptionally substituted by 1-6 R⁹⁹, C₇₋₁₆arylalkyl optionally substitutedby 1-6 R⁹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R⁹⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R⁹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R⁹⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-6 R⁹⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R⁹⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R⁹⁹; or any R⁷² and R⁷³may form, together with the nitrogen atom to which they are attached, a3-15 membered heterocycloalkyl optionally substituted by 1-6 R¹⁰⁹ or a5-15 membered heteroaryl optionally substituted by 1-6 R¹⁰⁹.

Embodiment 864

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁹⁹, phenyl optionally substituted by 1-3R⁹⁹, benzyl optionally substituted by 1-3 R⁹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R⁹⁹, and 5-10 membered heteroaryloptionally substituted by 1-3 R⁹⁹; or any R⁷² and R⁷³ may form, togetherwith the nitrogen atom to which they are attached, a 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁰⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-3 R¹⁰⁹

Embodiment 865

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁹⁹, phenyl optionally substituted by 1-3R⁹⁹, benzyl optionally substituted by 1-3 R⁹⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁹⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R⁹⁹, and 5-10 membered heteroaryloptionally substituted by 1-3 R⁹⁹.

Embodiment 866

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁹⁹, phenyl optionally substituted by 1-3R⁹⁹, benzyl optionally substituted by 1-3 R⁹⁹, C₃₋₆cycloalkyl optionallysubstituted by 1-3 R⁹⁹, 3-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁹⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁹⁹; or any R⁷² and R⁷³ may form, together with thenitrogen atom to which they are attached, a 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁰⁹ or a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁰⁹.

Embodiment 867

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁹⁹, phenyl optionally substituted by 1-3R⁹⁹, benzyl optionally substituted by 1-3 R⁹⁹, C₅₋₆cycloalkyl optionallysubstituted by 1-3 R⁹⁹, 5-6 membered heterocycloalkyl optionallysubstituted by 1-3 R⁹⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁹⁹.

Embodiment 868

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁹⁹, phenyl optionally substituted by 1-3R⁹⁹, benzyl optionally substituted by 1-3 R⁹⁹, 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R⁹⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R⁹⁹.

Embodiment 869

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyl,phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6membered heteroaryl; or any R⁷² and R⁷³ may form, together with thenitrogen atom to which they are attached, a 5-6 memberedheterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 870

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyl,phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6membered heteroaryl.

Embodiment 871

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁹⁹, phenyl optionally substituted by 1-3R⁹⁹, and benzyl optionally substituted by 1-3 R⁹⁹.

Embodiment 872

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H and C₁₋₆alkyloptionally substituted by 1-3 R⁹⁹.

Embodiment 873

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H, C₁₋₆alkyl,phenyl, and benzyl.

Embodiment 874

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is independently chosen from H and C₁₋₆alkyl.

Embodiment 875

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-861, wherein R⁷² andR⁷³ at each occurrence is H.

Embodiment 876

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R⁷⁸ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-13 R⁸⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁸⁹,C₂₋₆alkynyl optionally substituted by 1-9 R⁸⁹, C₆₋₁₁aryl optionallysubstituted by 1-11 R⁸⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R⁸⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁸⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁸⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R⁸⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R⁸⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R⁸⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R⁸⁹; or any two R⁷⁸attached to the same phosphorus atom can, together with the phosphorusatom linking them, form a 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R⁸⁹.

Embodiment 877

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R⁷⁸ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁸⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁸⁹,C₂₋₆alkynyl optionally substituted by 1-3 R⁸⁹, C₆₋₁₁aryl optionallysubstituted by 1-3 R⁸⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3R⁸⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R⁸⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-3 R⁸⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R⁸⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-3 R⁸⁹, 5-15 memberedheteroaryl optionally substituted by 1-3 R⁸⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-3 R⁸⁹; or any two R⁷⁸attached to the same phosphorus atom can, together with the phosphorusatom linking them, form a 3-10 membered heterocycloalkyl optionallysubstituted by 1-6 R⁸⁹.

Embodiment 878

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R⁷⁸ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁸⁹, C₂₋₆alkenyl optionally substituted by 1-3 R⁸⁹,C₂₋₆alkynyl optionally substituted by 1-3 R⁸⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R⁸⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R⁸⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R⁸⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R⁸⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R⁸⁹; or any two R⁷⁸ attached tothe same phosphorus atom can, together with the phosphorus atom linkingthem, form a 3-6 membered heterocycloalkyl optionally substituted by 1-3R⁸⁹.

Embodiment 879

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R⁷⁸ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁸⁹, C₆₋₁₀aryl optionally substituted by 1-3 R⁸⁹,C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁸⁹, C₃₋₁₀cycloalkyloptionally substituted by 1-3 R⁸⁹, 3-10 membered heterocycloalkyloptionally substituted by 1-3 R⁸⁹, and 5-10 membered heteroaryloptionally substituted by 1-3 R⁸⁹; or any two R⁷⁸ attached to the samephosphorus atom can, together with the phosphorus atom linking them,form a 3-6 membered heterocycloalkyl optionally substituted by 1-3 R⁸⁹.

Embodiment 880

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R⁷⁸ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁸⁹, phenyl optionally substituted by 1-3 R⁸⁹, benzyloptionally substituted by 1-3 R⁸⁹, C₃₋₆cycloalkyl optionally substitutedby 1-3 R⁸⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3R⁸⁹, and 5-6 membered heteroaryl optionally substituted by 1-3 R⁸⁹; orany two R⁷⁸ attached to the same phosphorus atom can, together with thephosphorus atom linking them, form a 3-6 membered heterocycloalkyloptionally substituted by 1-3 R⁸⁹.

Embodiment 881

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R⁷⁸ ateach occurrence is independently chosen from C₁₋₆alkyl, phenyl, benzyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl; or any two R⁷⁸ attached to the same phosphorus atom can,together with the phosphorus atom linking them, form a 6 memberedheterocycloalkyl optionally substituted by 1-3 R⁸⁹.

Embodiment 882

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R⁷⁸ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁸⁹, phenyl, and benzyl.

Embodiment 883

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R⁷⁸ ateach occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R⁸⁹, phenyl optionally substituted by 1-3 R⁸⁹, andbenzyl optionally substituted by 1-3 R⁸⁹; or any two R⁷⁸ attached to thesame phosphorus atom can, together with the phosphorus atom linkingthem, form a 6 membered heterocycloalkyl optionally substituted by 1-3R⁸⁹.

Embodiment 884

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R⁷⁸ ateach occurrence is independently chosen from C₁₋₆alkyl, phenyl, andbenzyl; or any two R⁷⁸ attached to the same phosphorus atom can,together with the phosphorus atom linking them, form an azaphosphinanering optionally substituted by 1-3 C₁₋₆alkyl.

Embodiment 885

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R⁷⁸ ateach occurrence is C₁₋₆alkyl optionally substituted by 1-3 R⁸⁹; or anytwo R⁷⁸ attached to the same phosphorus atom can, together with thephosphorus atom linking them, form an azaphosphinane ring optionallysubstituted by 1-3 R⁸⁹.

Embodiment 886

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-875, wherein R⁷⁸ ateach occurrence is C₁₋₆alkyl.

Embodiment 900

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹¹⁹,C₆₋₁₁aryl optionally substituted by 1-6 R¹¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-6 R¹¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R¹¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R¹¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-6 R¹¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-6 R¹¹⁹, 5-15membered heteroaryl optionally substituted by 1-6 R¹⁹, 6-21 memberedheteroarylalkyl optionally substituted by 1-6 R¹¹⁹, halogen, —CN,—C(═O)R¹¹⁰, —C(═O)OR¹¹⁰, —C(═O)NR¹¹²R¹¹³, —C(═O)C(═O)R¹¹⁰,—C(═NR¹¹⁵)R¹¹⁰, —C(═NR¹¹⁵)NR¹¹²R¹¹³, —C(═NOH)NR¹¹²R¹¹³, —C(═NOR¹¹⁶)R¹¹⁰,—C(═NNR¹¹²R¹¹³)R¹¹⁰, —C(═NNR¹¹⁴C(═O)R¹¹¹)R¹¹⁰,—C(═NNR¹¹⁴C(═O)OR¹¹¹)R¹¹⁰, —C(═S)NR¹¹²R¹¹³, —NC, —NO₂, —NR¹¹²R¹¹³,—NR¹¹⁴NR¹¹²R¹¹³, —N═NR¹¹⁴, ═NR¹¹⁰, ═NOR¹¹⁰, —NR¹¹⁴OR¹¹⁶,—NR¹¹⁴C(═O)R¹¹⁰, —NR¹¹⁴C(═O)C(═O)R¹¹⁰, —NR¹¹⁴C(═O)OR¹¹¹,—NR¹¹⁴C(═O)C(═O)OR¹¹¹, —NR¹¹⁴C(═O)NR¹¹²R¹¹³, —NR¹¹⁴C(═O)NR¹¹⁴C(═O)R¹¹⁰,—NR¹⁴C(═O)NR¹¹⁴C(═O)OR¹¹⁰, —NR¹⁴C(═NR¹¹⁵)NR¹¹²R¹¹³,—NR¹¹⁴C(═O)C(═O)NR¹¹²R¹¹³, —NR¹¹⁴C(═S)R¹¹⁰, —NR¹¹⁴C(═S)OR¹¹⁰,—NR¹¹⁴C(═S)NR¹¹²R¹¹³, —NR¹¹⁴S(═O)₂R¹¹, —NR¹¹⁴S(═O)₂NR¹¹²R¹¹³,—NR¹¹⁴P(═O)R¹¹⁸R¹¹⁸, —NR¹¹⁴P(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³),—NR¹¹⁴P(═O)(OR¹¹⁰)(OR¹¹⁰)—NR¹¹⁴P(═O)(SR¹¹⁰)(SR¹¹⁰), —OR¹⁰, ═O, —OCN,—OC(═O)R¹¹⁰, OC(═O)NR¹¹²R¹¹³, —OC(═O)OR¹¹⁰, —OC(═NR¹¹⁵)NR¹¹²R¹¹³,—OS(═O)R¹¹⁰, —OS(═O)₂R, —OS(═O)₂OR¹¹⁰, —OS(═O)₂NR¹¹²R¹¹³,—OP(═O)R¹¹⁸R¹¹⁸, —OP(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³), —OP(═O)(OR¹¹⁰)(OR¹¹⁰),—OP(═O)(SR¹¹⁰)(SR¹¹⁰), —Si(R¹¹⁴)₃, —SCN, ═S, —S(═O)_(n)R¹¹⁰,—S(═O)₂OR¹¹⁰, —SO₃R¹¹¹¹, —S(═O)₂NR¹¹²R¹¹³, —S(═O)NR¹¹²R¹¹³,—SP(═O)R¹¹⁸R¹¹⁸, —SP(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³), —SP(═O)(OR¹¹⁰)(OR¹¹⁰),—SP(═O)(SR¹¹⁰)(SR¹¹⁰), —P(═O)R¹¹⁸R¹¹⁸, —P(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³),—P(═O)(OR¹¹⁰)(OR¹¹⁰), and —P(═O)(SR¹¹⁰)(SR¹¹⁰).

Embodiment 901

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, C₆₋₁₁aryl optionallysubstituted by 1-6 R¹¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-6R¹¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-6 R¹¹⁹, 5-15 memberedheteroaryl optionally substituted by 1-6 R¹¹⁹, halogen, —CN, —C(═O)R¹¹⁰,—C(═O)OR¹¹⁰, —C(═O)NR¹¹²R¹¹³, —NC, —NO₂, —NR¹¹²R¹¹³, —NR¹¹⁴NR¹¹²R¹¹³,—NR¹¹⁴OR¹¹⁶, —NR¹¹⁴C(═O)R¹¹⁰, —NR¹¹⁴C(═O)OR¹¹¹, —NR¹¹⁴C(═O)NR¹¹²R¹¹³,—NR¹¹⁴C(═O)NR¹¹⁴C(═O)R¹¹⁰, —NR¹¹⁴S(═O)₂R¹¹¹, —NR¹¹⁴S(═O)₂NR¹¹²R¹¹³,—OR¹¹⁰, ═O, —OCN, —OC(═O)R¹¹⁰, —OC(═O)NR¹¹²R¹¹³, —OC(═O)OR¹¹⁰,—Si(R¹¹⁴)₃, —SCN, ═S, —S(═O)_(n)R¹¹⁰, and —S(═O)₂NR¹¹²R¹¹³.

Embodiment 902

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-6 R¹¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-6 R¹¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6R¹¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-6 R¹¹⁹, halogen, —CN, —C(═O)R¹¹⁰,—C(═O)OR¹¹⁰, —C(═O)NR¹¹²R¹¹³, —NO₂, —NR¹¹²R¹¹³, —NR¹¹⁴C(═O)R¹¹⁰,NR¹¹⁴C(═O)OR¹¹¹, —NR¹¹⁴C(═O)NR¹¹²R¹¹³, —NR¹¹⁴C(═O)NR¹¹⁴C(═O)R¹¹⁰,—NR¹¹⁴S(═O)₂R¹¹¹, —NR¹¹⁴S(═O)₂NR¹¹²R¹¹³, —OR¹¹⁰, ═O, —OC(═O)R¹¹⁰,—OC(═O)NR¹¹²R¹¹³, —OC(═O)OR¹¹⁰, —Si(R¹¹⁴)₃, —S(═O)_(n)R¹¹⁰, and—S(═O)₂NR¹¹²R¹¹³.

Embodiment 903

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R¹¹⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R¹¹⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R¹¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R¹¹⁹, halogen, —CN, —C(═O)R¹¹⁰,—C(═O)OR¹¹⁰, —C(═O)NR¹¹²R¹¹³, —NO₂, —NR¹¹²R¹¹³, —NR¹¹⁴C(═O)R¹¹⁰,—NR¹¹⁴C(═O)OR¹¹¹, —NR¹¹⁴C(═O)NR¹¹²R¹¹³, —NR¹¹⁴C(═O)NR¹¹⁴C(═O)R¹¹⁰,—NR¹¹⁴S(═O)₂R¹¹¹, —NR¹¹⁴S(═O)₂NR¹¹²R¹¹³, —OR¹¹⁰, ═O, —OC(═O)R¹¹⁰,—OC(═O)NR¹¹²R¹¹³, —OC(═)OR¹¹⁰, —Si(R¹¹⁴)₃, —S(═O)_(n)R¹¹⁰, and—S(═O)₂NR¹¹²R¹¹³.

Embodiment 904

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R¹¹⁹, phenyl optionallysubstituted by 1-3 R¹¹⁹, benzyl optionally substituted by 1-3 R¹¹⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R¹¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹¹⁹, halogen, —CN, —C(═O)R¹¹,—C(═O)OR¹¹⁰, —C(═O)NR¹¹²R¹¹³, —NO₂, —NR¹¹²R¹¹³, NR¹¹⁴C(═O)R¹¹⁰,—NR¹¹⁴C(═O)OR¹¹¹, —NR¹¹⁴C(═O)NR¹¹²R¹¹³, —NR¹¹⁴C(═O)NR¹¹⁴C(═O)R¹¹⁰,—NR¹¹⁴S(═O)₂R¹¹¹, —NR¹¹⁴S(═O)₂NR¹¹²R¹¹³, —OR¹⁰, ═O, —OC(═O)R¹¹⁰,—OC(═O)NR¹¹²R¹¹³, —OC(═O)OR¹¹⁰, —Si(R¹¹⁴)₃, —S(═)_(n)R¹¹⁰, and—S(═O)₂NR¹¹²R¹¹³.

Embodiment 905

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R¹¹⁹, phenyl optionallysubstituted by 1-3 R¹¹⁹, benzyl optionally substituted by 1-3 R¹¹⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R¹¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹¹⁹, halogen, —CN, —C(═O)R¹¹,—C(═O)OR¹¹⁰, —C(═O)NR¹¹²R¹¹³, —NO₂, —NR¹¹²R¹¹³, —NR¹¹⁴C(═O)R¹¹¹,—NR¹¹⁴S(═O)₂R¹¹¹, —OR¹¹⁰, —OC(═O)R¹¹⁰, —OC(═O)NR¹¹²R¹¹³, —S(═O)_(n)R¹¹⁰,and —S(═O)₂NR¹¹²R¹¹³.

Embodiment 906

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl, phenyl, benzyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R¹¹⁰,—C(═O)OR¹¹⁰, —C(═O)NR¹¹²R¹¹³, —NO₂, —NR¹¹²R¹¹³, —NR¹¹⁴C(═O)R¹¹⁰,—NR¹¹⁴S(═O)₂R¹¹¹, —OR¹¹⁰, —OC(═O)R¹¹⁰, —OC(═O)NR¹¹²R¹¹³, —S(═O)_(n)R¹¹⁰,and —S(═O)₂NR¹¹²R¹¹³.

Embodiment 907

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl, phenyl, benzyl, halogen, —CN, —C(═O)OR¹¹⁰, —C(═O)NR¹¹²R¹¹³,—NO₂, —NR¹¹²R¹¹³, —OR¹¹⁰, and —S(═O)_(n)R¹¹⁰.

Embodiment 908

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R¹¹⁹, phenyl optionallysubstituted by 1-3 R¹¹⁹, benzyl optionally substituted by 1-3 R¹¹⁹,halogen, —CN, —C(═O)OR¹¹⁰, —C(═O)NR¹¹²R¹¹³, —NO₂, —NR¹¹²R¹¹³, —OR¹¹⁰,and —S(═O)_(n)R¹¹⁰.

Embodiment 909

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl, phenyl, benzyl, halogen, —NR¹¹²R¹¹³ and —OR¹¹⁰

Embodiment 910

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl, halogen, —NR¹²R¹¹³, and —OR¹¹⁰.

Embodiment 911

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R¹¹⁹ and halogen.

Embodiment 912

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R¹¹⁹.

Embodiment 913

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, or 850-886, wherein R⁷⁹,R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently C₁₋₆alkyl.

Embodiment 914

The compound of any of Embodiments 1-156, 200-250, 300-371,

400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or900-913, wherein R¹¹⁰, R¹¹¹, R¹¹⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R¹²⁹, C₂₋₆alkenyl optionally substituted by 1-11R¹²⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹²⁹, C₆₋₁₁aryloptionally substituted by 1-11 R¹²⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹²⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹²⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹²⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹²⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹²⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹²⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹²⁹

Embodiment 915

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913,wherein R¹¹⁰, R¹¹¹, R⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹²⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹²⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹²⁹, C₆₋₁₀aryl optionally substituted by1-6 R¹²⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹²⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹²⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹²⁹, and 5-10 memberedheteroaryl optionally substituted by 1-6 R¹²⁹

Embodiment 916

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913,wherein R¹¹⁰, R¹¹¹, R¹¹⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹²⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹²⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹²⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹²⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹²⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹²⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹²⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R¹²⁹

Embodiment 917

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913,wherein R¹¹⁰, R¹¹¹, R⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹²⁹, phenyl optionally substituted by 1-3 R¹²⁹, benzyl optionallysubstituted by 1-3 R¹²⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹²⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹²⁹,and 5-10 membered heteroaryl optionally substituted by 1-3 R¹²⁹.

Embodiment 918

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913,wherein R¹¹⁰, R¹¹¹, R¹¹⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl, benzyl, C₃₋₁₀cycloalkyl,3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 919

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913,wherein R¹¹⁰, R¹¹¹, R¹¹⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹²⁹, phenyl optionally substituted by 1-3 R¹²⁹, benzyl optionallysubstituted by 1-3 R¹²⁹, C₅₋₆cycloalkyl optionally substituted by 1-3R¹²⁹, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R¹²⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R¹²⁹

Embodiment 920

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913,wherein R¹¹⁰, R¹¹¹, R¹¹⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence isindependently chosen from H, C₁-6alkyl, phenyl, benzyl, C₅₋₆cycloalkyl,5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 921

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913,wherein R¹¹⁰, R¹¹¹, R⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence isindependently chosen from H, C₁-6alkyl, phenyl, C₅₋₆cycloalkyl, 5-6membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 922

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913,wherein R¹¹⁰, R¹¹¹, R⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence isindependently chosen from H, C₁-6alkyl, phenyl, benzyl, C₅₋₆cycloalkyl,5-6 membered heterocycloalkyl optionally substituted by 1 R¹²⁹, and 5-6membered heteroaryl.

Embodiment 923

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913,wherein R¹¹⁰, R¹¹¹, R⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence isindependently chosen from H and C₁-6alkyl optionally substituted by 1-3R¹²⁹

Embodiment 924

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913,wherein R¹¹⁰, R¹¹¹, R¹¹⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence isindependently chosen from H and C₁-6alkyl.

Embodiment 925

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-913,wherein R¹¹⁰, R¹¹¹, R⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence is H.

Embodiment 926

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹² and R¹¹³ at each occurrence is independently chosen from H,C₁-6alkyl optionally substituted by 1-13 R¹³⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R¹³⁹, C₂₋₆alkynyl optionally substituted by 1-9R¹³⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹³⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R¹³⁹, C₃₋₁₁ optionally substituted by1-21 R¹³⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹³⁹,3-15 membered heterocycloalkyl optionally substituted by 1-28 R¹³⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹³⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹³⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹³⁹; or anyR¹¹² and R¹¹³ may form, together with the nitrogen atom to which theyare attached, a 3-15 membered heterocycloalkyl optionally substituted by1-28 R¹⁴⁹ or a 5-15 membered heteroaryl optionally substituted by 1-15R¹⁴⁹.

Embodiment 927

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹² and R¹¹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹³⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹³⁹, C₂₋₆alkynyl optionally substituted by 1-6 R³⁹,C₆₋₁₁aryl optionally substituted by 1-6 R¹³⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-6 R¹³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R¹³⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R¹³⁹, 3-15membered heterocycloalkyl optionally substituted by 1-6 R¹³⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-6 R¹³⁹, 5-15membered heteroaryl optionally substituted by 1-6 R¹³⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-6 R¹³⁹; or any R²and R¹¹³ may form, together with the nitrogen atom to which they areattached, a 3-15 membered heterocycloalkyl optionally substituted by 1-6R¹⁴⁹ or a 5-15 membered heteroaryl optionally substituted by 1-6 R¹⁴⁹.

Embodiment 928

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹² and R¹¹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹³⁹, phenyl optionallysubstituted by 1-3 R¹³⁹, benzyl optionally substituted by 1-3 R¹³⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹³⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹³⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R¹³⁹; or any R¹¹² and R¹¹³ mayform, together with the nitrogen atom to which they are attached, a 3-15membered heterocycloalkyl optionally substituted by 1-3 R¹⁴⁹ or a 5-15membered heteroaryl optionally substituted by 1-3 R¹⁴⁹.

Embodiment 929

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹² and R¹¹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹³⁹, phenyl optionallysubstituted by 1-3 R¹³⁹, benzyl optionally substituted by 1-3 R¹³⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹³⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹³⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R¹³⁹.

Embodiment 930

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹² and R¹¹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹³⁹, phenyl optionallysubstituted by 1-3 R¹³⁹, benzyl optionally substituted by 1-3 R¹³⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R¹³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹³⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R¹³⁹; or any R¹¹² and R¹¹³ mayform, together with the nitrogen atom to which they are attached, a 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁴⁹ or a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁴⁹.

Embodiment 931

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹² and R¹¹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹³⁹, phenyl optionallysubstituted by 1-3 R¹³⁹, benzyl optionally substituted by 1-3 R¹³⁹,C₅₋₆cycloalkyl optionally substituted by 1-3 R¹³⁹, 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹³⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R¹³⁹.

Embodiment 932

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹² and R¹¹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹³⁹, phenyl optionallysubstituted by 1-3 R¹³⁹, benzyl optionally substituted by 1-3 R¹³⁹, 5-6membered heterocycloalkyl optionally substituted by 1-3 R¹³⁹, and 5-6membered heteroaryl optionally substituted by 1-3 R¹³⁹.

Embodiment 933

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹¹² and R¹¹³ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl; or any R¹¹² and R¹¹³ mayform, together with the nitrogen atom to which they are attached, a 5-6membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 934

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹² and R¹¹³ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 935

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹² and R¹¹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹³⁹, phenyl optionallysubstituted by 1-3 R¹³⁹, and benzyl optionally substituted by 1-3 R¹³⁹.

Embodiment 936

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹² and R¹¹³ at each occurrence is independently chosen from Hand C₁₋₆alkyl optionally substituted by 1-3 R¹³⁹.

Embodiment 937

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹¹² and R¹¹³ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, and benzyl.

Embodiment 938

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹² and R¹¹³ at each occurrence is independently chosen from Hand C₁₋₆alkyl.

Embodiment 939

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-925,wherein R¹¹² and R¹¹³ at each occurrence is H.

Embodiment 940

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939,wherein R¹¹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-13 R¹²⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R¹²⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹²⁹, C₆₋₁₁aryloptionally substituted by 1-11 R¹²⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹²⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹²⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹²⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹²⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹²⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹²⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹²⁹

Embodiment 941

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939,wherein R¹¹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹²⁹, C₂₋₆alkenyl optionally substitutedby 1-3 R¹²⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹²⁹, C₆₋₁₁aryloptionally substituted by 1-3 R¹²⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-3 R¹²⁹, C₃₋₁₁ cycloalkyl optionally substituted by 1-3R¹²⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-3 R¹²⁹, 3-15membered heterocycloalkyl optionally substituted by 1-3 R¹²⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-3 R¹²⁹, 5-15membered heteroaryl optionally substituted by 1-3 R¹²⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-3 R¹²⁹

Embodiment 942

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939,wherein R¹¹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹²⁹, C₂₋₆alkenyl optionally substitutedby 1-3 R¹²⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹²⁹, C₆₋₁₀aryloptionally substituted by 1-3 R¹²⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-3 R¹²⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹²⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹²⁹,and 5-10 membered heteroaryl optionally substituted by 1-3 R¹²⁹

Embodiment 943

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939,wherein R¹¹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹²⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹²⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹²⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹²⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹²⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R¹²⁹

Embodiment 944

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939,wherein R¹¹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹²⁹, phenyl optionally substituted by 1-3R¹²⁹, benzyl optionally substituted by 1-3 R¹²⁹, C₃-6cycloalkyloptionally substituted by 1-3 R¹²⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R¹²⁹, and 5-6 membered heteroaryloptionally substituted by 1-3 R¹²⁹.

Embodiment 945

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939,wherein R¹¹⁸ at each occurrence is independently chosen from C₁₋₆alkyl,phenyl, benzyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6membered heteroaryl.

Embodiment 946

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939,wherein R¹¹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹²⁹, phenyl, and benzyl.

Embodiment 947

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939,wherein R¹¹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹²⁹, phenyl optionally substituted by 1-3R¹²⁹, and benzyl optionally substituted by 1-3 R¹²⁹

Embodiment 948

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939,wherein R¹¹⁸ at each occurrence is independently chosen from C₁₋₆alkyl,phenyl, and benzyl.

Embodiment 949

The compound of any of Embodiments 1-156, 200-250, 300-371,

400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or900-939, wherein R¹¹⁸ at each occurrence is C₁₋₆alkyl optionallysubstituted by 1-3 R¹²⁹

Embodiment 950

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-939,wherein R¹¹⁸ at each occurrence is C₁₋₆alkyl.

Embodiment 951

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, —R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R¹⁵⁹, C₂₋₆alkenyloptionally substituted by 1-6 R¹⁵⁹, C₂₋₆alkynyl optionally substitutedby 1-6 R¹⁵⁹, C₆₋₁₁aryl optionally substituted by 1-6 R¹⁵⁹,C₇₋₁₆arylalkyl optionally substituted by 1-6 R¹⁵⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-6 R¹⁵⁹, C₄₋₁₇cycloalkylalkyl optionallysubstituted by 1-6 R¹⁵⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁵⁹, 4-21 membered heterocycloalkylalkyl optionallysubstituted by 1-6 R¹⁵⁹, 5-15 membered heteroaryl optionally substitutedby 1-6 R¹⁵⁹, 6-21 membered heteroarylalkyl optionally substituted by 1-6R¹⁵⁹, halogen, —CN, —C(═O)R¹⁵⁰, —C(═O)OR¹⁵⁰, —C(═O)NR¹⁵²R¹⁵³,—(═O)C(═O)R¹⁵⁰, —C(═NR¹⁵⁵)R¹⁵⁰, —C(═NR¹⁵⁵)NR¹⁵²R¹⁵³, —C(═NOH)NR¹⁵²R¹⁵³,—C(═NOR¹⁵⁶)R¹⁵⁰, —C(═NNR¹⁵²R¹⁵³)R¹⁵⁰, —C(═NNR¹⁵⁴C(═O)R¹⁵¹)R¹⁵⁰,—C(═NNR¹⁵⁴C(═O)OR¹⁵¹)R¹⁵⁰, —C(═S)NR¹⁵²R¹⁵³, —NC, —NO₂, —NR¹⁵²R¹⁵³,NR¹⁵⁴NR¹⁵²R¹⁵³, —N═NR¹⁵⁴, ═NR¹⁵⁰, ═NOR¹⁵⁰, —NR¹⁵⁴OR¹⁵⁶, —NR¹⁵⁴C(═O)R¹⁵⁰,—NR¹⁵⁴C(═O)C(═O)R¹⁵⁰, —NR¹⁵⁴C(═O)OR¹⁵¹, —NR¹⁵⁴C(═O)C(═O)OR¹⁵¹,—NR¹⁵⁴C(═O)NR¹⁵²R¹⁵³, —NR¹⁵⁴C(═O)NR¹⁵⁴C(═O)R¹⁵⁰,—NR¹⁵⁴C(═O)NR¹⁵⁴C(═O)OR¹⁵⁰, —NR¹⁵⁴C(═NR¹⁵⁵)NR¹⁵²R¹⁵³,—NR¹⁵⁴C(═O)C(═O)NR¹⁵²R¹⁵³, NR¹⁵⁴C(═S)R¹⁵⁰, —NR¹⁵⁴C(═S)OR¹⁵⁰,—NR¹⁵⁴C(═S)NR¹⁵²R¹⁵³, —NR¹⁵⁴S(═O)₂R¹⁵¹, —NR¹⁵⁴S(═O)₂NR¹⁵²R¹⁵,—NR¹⁵⁴P(═O)R¹⁵⁸R¹⁵, —NR¹⁵⁴P(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³),—NR¹⁵⁴P(═)(OR¹⁵⁰)(OR¹⁵⁰), —NR¹⁵⁴P(═O)(SR¹⁵⁰)(SR¹⁵⁰), —OR¹⁵⁰, ═O, —OCN,—OC(═O)R¹⁵⁰, —OC(═O)NR¹⁵²R¹⁵³, —OC(═O)OR¹⁵⁰, —OC(═NR¹⁵⁵)NR¹⁵²R¹⁵³,—OS(═O)R¹⁵⁰, —OS(═O)₂R¹⁵⁰, —OS(═O)₂OR¹⁵⁰, —OS(═O)₂NR¹⁵²R¹⁵³,—OP(═O)R¹⁵⁸R¹⁵⁸, —OP(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³), —OP(═O)(OR¹⁵⁰)(OR¹⁵⁰),—OP(═O)(SR¹⁵⁰)(SR¹⁵⁰), —Si(R¹⁵⁴)₃, —SCN, ═S, —S(═O)_(n)R, —S(═O)₂OR¹⁵⁰,—SO₃R¹⁵¹⁵, —S(═O)₂NR¹⁵²R¹⁵³, —S(═O)NR¹⁵²R¹⁵³, —SP(═O)R¹⁵⁸R¹⁵⁸,—SP(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³), —SP(═O)(OR¹⁵⁰)(OR¹⁵⁰),—SP(═O)(SR¹⁵⁰)(SR¹⁵⁰), —P(═O)R¹⁵⁸R¹⁵⁸, —P(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³),—P(═O)(OR¹⁵⁰)(OR¹⁵⁰), and —P(═O)(SR¹⁵⁰)(SR¹⁵⁰).

Embodiment 952

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, —R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R¹⁵⁹, C₆₋₁₁aryloptionally substituted by 1-6 R¹⁵⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-6 R¹⁵⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R¹⁵⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R¹⁵⁹,5-15 membered heteroaryl optionally substituted by 1-6 R¹⁵⁹, halogen,—CN, —C(═O)R¹⁵⁰, —C(═O)OR¹⁵⁰, —C(═O)NR¹⁵²R¹⁵³, —NC, —NO₂, —NR¹⁵²R¹⁵³,—NR¹⁵⁴NR¹⁵²R¹⁵³, —NR¹⁵⁴OR¹⁵⁶, —NR¹⁵⁴C(═O)R¹⁵⁰, —NR¹⁵⁴C(═O)OR¹⁵¹,—NR¹⁵⁴C(═O)NR¹⁵²R¹⁵³, —NR¹⁵⁴C(═O)NR¹⁵⁴C(═O)R¹⁵⁰, NR¹⁵⁴S(═O)₂R¹⁵¹,—NR¹⁵⁴S(═O)NR¹⁵²R¹⁵³, —OR¹⁵⁰, ═O, —OCN, —OC(═O)R¹⁵⁰, —OC(═O)NR¹⁵²R¹⁵³,—OC(═O)OR¹⁵⁰, —Si(R¹⁵⁴)₃, —SCN, ═S, —S(═)_(n)R¹⁵⁰, and —S(═O)₂NR¹⁵²R¹⁵³.

Embodiment 953

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, —R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R¹⁵⁹, C₆₋₁₀aryloptionally substituted by 1-6 R¹⁵⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-6 R¹⁵⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6R¹⁵⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁵⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁵⁹, halogen,—CN, —C(═O)R¹⁵⁰, —C(═O)OR¹⁵⁰, —C(═O)NR¹⁵²R¹⁵³, —NO₂, —NR¹⁵²R¹⁵³,—NR¹⁵⁴C(═O)R¹⁵⁰, —NR¹⁵⁴C(═O)OR¹⁵¹, —NR¹⁵⁴C(═O)NR¹⁵²R¹⁵³,—NR^(154C)(═O)NR¹⁵⁴C(═O)R¹⁵⁰, —NR¹⁵⁴S(═O)₂R¹⁵¹, —NR¹⁵⁴S(═O)₂NR¹⁵²R¹⁵³,—OR¹⁵⁰, ═O, —OC(═O)R¹⁵⁰, —OC(═O)NR¹⁵²R¹⁵³, —OC(═O)OR¹⁵⁰, —Si(R¹⁵⁴)³,—S(═O)_(n)R¹⁵⁰, and —S(═O)₂NR¹⁵²R¹⁵³.

Embodiment 954

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁵⁹, C₆₋₁₀aryloptionally substituted by 1-3 R¹⁵⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-3 R¹⁵⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁵⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁵⁹,5-10 membered heteroaryl optionally substituted by 1-3 R¹⁵⁹, halogen,—CN, —C(═O)R¹⁵⁰, —C(═O)OR¹⁵⁰, —C(═O)NR¹⁵²R¹⁵³, —NO₂, —NR¹⁵²R¹⁵³,—NR¹⁵⁴C(═O)R¹⁵⁰, —NR¹⁵⁴C(═O)OR¹⁵¹, —NR¹⁵⁴C(═O)NR¹⁵²R¹⁵³,—NR¹⁵⁴C(═O)NR¹⁵⁴C(═O)R¹⁵⁰, —NR¹⁵⁴S(═O)₂R¹⁵¹, —NR¹⁵⁴S(═O)₂NR¹⁵²R¹⁵³,—OR¹⁵⁰, ═O, —OC(═O)R¹⁵⁰, —OC(═O)NR¹⁵²R¹⁵³, —OC(═O)OR, —Si(R¹⁵⁴)₃,—S(═O)_(n)R¹⁵⁰, and —S(═O)₂NR¹⁵²R¹⁵³.

Embodiment 955

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁵⁹, phenyloptionally substituted by 1-3 R¹⁵⁹, benzyl optionally substituted by 1-3R¹⁵⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁵⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁵⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁵⁹, halogen, —CN, —C(═O)R¹⁵⁰,—C(═O)OR¹⁵⁰, —C(═O)NR¹⁵²R¹⁵³, —NO₂, —NR¹⁵²R¹⁵³, —NR¹⁵⁴C(═O)R¹⁵⁰,—NR¹⁵⁴C(═O)OR¹⁵¹, —NR¹⁵⁴C(═O)NR¹⁵²R¹⁵³, —NR¹⁵⁴C(═O)NR¹⁵⁴C(═O)R¹⁵⁰,—NR¹⁵⁴S(═O)₂R¹⁵¹, —NR¹⁵⁴S(═O)₂NR¹⁵²R¹⁵³, —OR¹⁵⁰, ═O, —OC(═O)R¹⁵⁰,—OC(═O)NR¹⁵²R¹⁵³, —OC(═O)OR¹⁵⁰, —Si(R¹⁵⁴)₃, —S(═O)_(n)R¹⁵⁰, and—S(═O)₂NR¹⁵²R¹⁵³.

Embodiment 956

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁵⁹, phenyloptionally substituted by 1-3 R¹⁵⁹, benzyl optionally substituted by 1-3R¹⁵⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁵⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁵⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁵⁹, halogen, —CN, —C(═O)R¹⁵⁰,—C(═)OR¹⁵⁰, —C(═O)NR¹⁵²R¹⁵³, —NO₂, —NR¹⁵²R¹⁵³, —NR¹⁵⁴C(═O)R¹⁵⁰,—NR¹⁵⁴S(═O)₂R¹⁵¹, —OR¹⁵⁰, —OC(═O)R¹⁵⁰, —OC(═O)NR¹⁵²R¹⁵³, —S(═O)_(n)R¹⁵⁰,and —S(═O)₂NR¹⁵²R¹⁵³.

Embodiment 957

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl, phenyl, benzyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R⁵⁰,—C(═O)OR¹⁵⁰, —C(═O)NR¹⁵²R¹⁵³, —NO₂, —NR¹⁵²R¹⁵, —NR¹⁵⁴C(═O)R¹⁵⁰,—NR¹⁵⁴S(═O)₂R¹⁵¹, —OR¹⁵⁰, —OC(═O)R, —OC(═O)NR R, —S(═O)_(n)R¹⁵⁰, and—S(═O)₂NR¹⁵²R¹⁵³.

Embodiment 958

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl, phenyl, benzyl, halogen, —CN, —C(═O)OR⁵,—C(═O)NR¹⁵²R¹⁵³, —NO₂, —NR¹⁵²R¹⁵³, —OR¹⁵⁰, and —S(═O)_(n)R¹⁵.

Embodiment 959

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁵⁹, phenyloptionally substituted by 1-3 R¹⁵⁹, benzyl optionally substituted by 1-3R¹⁵⁹, halogen, —CN, —C(═O)OR¹⁵⁰, —C(═O)NR¹⁵²R¹⁵³, —NO₂, —NR¹⁵²R¹⁵³,—OR¹⁵⁰, and —S(═O)_(n)R¹⁵⁰

Embodiment 960

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl, phenyl, benzyl, halogen, —NR¹⁵²R¹⁵³, and —OR¹⁵⁰.

Embodiment 961

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl, halogen, —NR¹⁵²R¹⁵³, and —OR¹⁵⁰.

Embodiment 962

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁵⁹ and halogen.

Embodiment 963

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁵⁹.

Embodiment 964

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-950,wherein R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independentlyC₁₋₆alkyl.

Embodiment 965

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁶⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁶⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁶⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁶⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁶⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁶⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁶⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁶⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R¹⁶⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁶⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R¹⁶⁹

Embodiment 966

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R¹⁶⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁶⁹, C₂₋₆alkynyloptionally substituted by 1-6 R¹⁶⁹, C₆₋₁₀aryl optionally substituted by1-6 R¹⁶⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R¹⁶⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁶⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R¹⁶⁹, and 5-10 memberedheteroaryl optionally substituted by 1-6 R¹⁶⁹.

Embodiment 967

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁶⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁶⁹, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁶⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁶⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁶⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁶⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁶⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁶⁹.

Embodiment 968

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁶⁹, phenyl optionally substituted by 1-3 R¹⁶⁹, benzyl optionallysubstituted by 1-3 R¹⁶⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁶⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁶⁹,and 5-10 membered heteroaryl optionally substituted by 1-3 R⁶⁹.

Embodiment 969

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl, benzyl, C₃₋₁₀cycloalkyl,3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 970

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R⁵⁴, R¹⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁶⁹, phenyl optionally substituted by 1-3 R¹⁶⁹, benzyl optionallysubstituted by 1-3 R¹⁶⁹, C₅₋₆cycloalkyl optionally substituted by 1-3R¹⁶⁹, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R¹⁶⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R¹⁶⁹

Embodiment 971

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl,5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 972

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl, C₅₋₆cycloalkyl, 5-6membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 973

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl,5-6 membered heterocycloalkyl optionally substituted by 1 R¹⁶⁹, and 5-6membered heteroaryl.

Embodiment 974

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R¹⁶⁹.

Embodiment 975

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl.

Embodiment 976

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-964,wherein R¹⁵⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence is H.

Embodiment 977

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R¹⁷⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R¹⁷⁹, C₂₋₆alkynyl optionally substituted by 1-9R¹⁷⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁷⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R¹⁷⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R¹⁷⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by1-32 R¹⁷⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28R¹⁷⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40R¹⁷⁹, 5-15 membered heteroaryl optionally substituted by 1-15 R¹⁷⁹, and6-21 membered heteroarylalkyl optionally substituted by 1-27 R¹⁷⁹; orany R¹⁵² and R¹⁵³ may form, together with the nitrogen atom to whichthey are attached, a 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R¹⁸⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R¹⁸⁹.

Embodiment 978

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R¹⁷⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R¹⁷⁹, C₂₋₆alkynyl optionally substituted by 1-6 R¹⁷⁹,C₆₋₁₁aryl optionally substituted by 1-6 R¹⁷⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-6 R¹⁷⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R¹⁷⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R¹⁷⁹, 3-15membered heterocycloalkyl optionally substituted by 1-6 R¹⁷⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-6 R¹⁷⁹, 5-15membered heteroaryl optionally substituted by 1-6 R¹⁷⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-6 R¹⁷⁹; or any R¹⁵²and R¹⁵³ may form, together with the nitrogen atom to which they areattached, a 3-15 membered heterocycloalkyl optionally substituted by 1-6R¹⁸⁹ or a 5-15 membered heteroaryl optionally substituted by 1-6 R¹⁸⁹.

Embodiment 979

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁷⁹, phenyl optionallysubstituted by 1-3 R¹⁷⁹, benzyl optionally substituted by 1-3 R¹⁷⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁷⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁷⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁷⁹; or any R¹⁵² and R¹⁵³ mayform, together with the nitrogen atom to which they are attached, a 3-15membered heterocycloalkyl optionally substituted by 1-3 R¹⁸⁹ or a 5-15membered heteroaryl optionally substituted by 1-3 R¹⁸⁹.

Embodiment 980

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁷⁹, phenyl optionallysubstituted by 1-3 R¹⁷⁹, benzyl optionally substituted by 1-3 R¹⁷⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁷⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁷⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁷⁹.

Embodiment 981

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁷⁹, phenyl optionallysubstituted by 1-3 R¹⁷⁹, benzyl optionally substituted by 1-3 R¹⁷⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁷⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁷⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁷⁹; or any R¹⁵² and R¹⁵³ mayform, together with the nitrogen atom to which they are attached, a 3-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁸⁹ or a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁸⁹.

Embodiment 982

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁷⁹, phenyl optionallysubstituted by 1-3 R¹⁷⁹, benzyl optionally substituted by 1-3 R¹⁷⁹,C₅₋₆cycloalkyl optionally substituted by 1-3 R¹⁷⁹, 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁷⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁷⁹.

Embodiment 983

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁷⁹, phenyl optionallysubstituted by 1-3 R¹⁷⁹, benzyl optionally substituted by 1-3 R¹⁷⁹, 5-6membered heterocycloalkyl optionally substituted by 1-3 R¹⁷⁹, and 5-6membered heteroaryl optionally substituted by 1-3 R¹⁷⁹.

Embodiment 984

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl; or any R¹⁵² and R¹⁵³ mayform, together with the nitrogen atom to which they are attached, a 5-6membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 985

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 986

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁷⁹, phenyl optionallysubstituted by 1-3 R¹⁷⁹, and benzyl optionally substituted by 1-3 R¹⁷⁹.

Embodiment 987

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from Hand C₁₋₆alkyl optionally substituted by 1-3 R¹⁷⁹.

Embodiment 988

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, and benzyl.

Embodiment 989

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is independently chosen from Hand C₁₋₆alkyl.

Embodiment 990

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-976,wherein R¹⁵² and R¹⁵³ at each occurrence is H.

Embodiment 991

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990,wherein R¹⁵⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-13 R¹⁶⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R¹⁶⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹⁶⁹, C₆₋₁₁aryloptionally substituted by 1-11 R¹⁶⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹⁶⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹⁶⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁶⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹⁶⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹⁶⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹⁶⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹⁶⁹.

Embodiment 992

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990,wherein R¹⁵⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹⁶⁹, C₂₋₆alkenyl optionally substitutedby 1-3 R¹⁶⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁶⁹, C₆₋₁₁aryloptionally substituted by 1-3 R¹⁶⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-3 R¹⁶⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3R¹⁶⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-3 R¹⁶⁹, 3-15membered heterocycloalkyl optionally substituted by 1-3 R¹⁶⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-3 R¹⁶⁹, 5-15membered heteroaryl optionally substituted by 1-3 R¹⁶⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-3 R¹⁶⁹.

Embodiment 993

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990,wherein R¹⁵⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹⁶⁹, C₂₋₆alkenyl optionally substitutedby 1-3 R¹⁶⁹, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁶⁹, C₆₋₁₀aryloptionally substituted by 1-3 R¹⁶⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-3 R¹⁶⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁶⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁶⁹,and 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁶⁹.

Embodiment 994

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990,wherein R¹⁵⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹⁶⁹, C₆₋₁₀aryl optionally substituted by1-3 R¹⁶⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R¹⁶⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R¹⁶⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁶⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁶⁹.

Embodiment 995

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990,wherein R¹⁵⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹⁶⁹, phenyl optionally substituted by 1-3R¹⁶⁹, benzyl optionally substituted by 1-3 R¹⁶⁹, C₃₋₆cycloalkyloptionally substituted by 1-3 R¹⁶⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁶⁹, and 5-6 membered heteroaryloptionally substituted by 1-3 R¹⁶⁹.

Embodiment 996

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990,wherein R¹⁵⁸ at each occurrence is independently chosen from C₁₋₆alkyl,phenyl, benzyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6membered heteroaryl.

Embodiment 997

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990,wherein R¹⁵⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹⁶⁹, phenyl, and benzyl.

Embodiment 998

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990,wherein R¹⁵⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R¹⁶⁹, phenyl optionally substituted by 1-3R¹⁶⁹, and benzyl optionally substituted by 1-3 R¹⁶⁹.

Embodiment 999

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990,wherein R¹⁵⁸ at each occurrence is independently chosen from C₁₋₆alkyl,phenyl, and benzyl.

Embodiment 1000

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990,wherein R¹⁵⁸ at each occurrence is C₁₋₆alkyl optionally substituted by1-3 R¹⁶⁹.

Embodiment 1001

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-990,wherein R¹⁵⁸ at each occurrence is C₁₋₆alkyl.

Embodiment 1002

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R¹⁹⁹, C₂₋₆alkenyloptionally substituted by 1-6 R¹⁹⁹, C₂₋₆alkynyl optionally substitutedby 1-6 R¹⁹⁹, C₆₋₁₁aryl optionally substituted by 1-6 R¹⁹⁹,C₇₋₁₆arylalkyl optionally substituted by 1-6 R¹⁹⁹, C₃₋₁₁cycloalkyloptionally substituted by 1-6 R¹⁹⁹, C₄₋₁₇cycloalkylalkyl optionallysubstituted by 1-6 R¹⁹⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-6 R¹⁹⁹, 4-21 membered heterocycloalkylalkyl optionallysubstituted by 1-6 R¹⁹⁹, 5-15 membered heteroaryl optionally substitutedby 1-6 R¹⁹⁹, 6-21 membered heteroarylalkyl optionally substituted by 1-6R¹⁹⁹, halogen, —CN, —C(═O)R¹⁹⁰, —C(═)OR¹⁹⁰, —C(═O)NR¹⁹²R¹⁹³,—(═O)C(═O)R¹⁹⁰, —C(═NR¹⁹⁵)R¹⁹⁰, —C(═NR¹⁹⁵)NR¹⁹²R¹⁹³, —C(═NOH)NR¹⁹²R¹⁹³,—C(═NOR¹⁹⁶)R¹⁹⁰, —C(═NNR¹⁹²R¹⁹³)R¹⁹⁰, —C(═NNR¹⁹⁴C(═O)R¹⁹¹)R¹⁹⁰,—C(═NNR¹⁹⁴C(═O)OR¹⁹¹)R¹⁹⁰, —C(═S)NR¹⁹²R¹⁹³, —NC, —NO₂, —NR¹⁹²R¹⁹³,—NR¹⁹⁴NR¹⁹²R¹⁹³, —N═NR¹⁹⁴, ═NR¹⁹⁰, ═NOR¹⁹⁰, —NR¹⁹⁴OR¹⁹⁶, NR¹⁹⁴C(═O)R¹⁹⁰,—NR¹⁹⁴C(═O)C(═O)R¹⁹⁰, —NR¹⁹⁴C(═O)OR, —NR¹⁹⁴C(═O)C(═O)OR¹⁹¹,—NR¹⁹⁴C(═O)NR¹⁹²R¹⁹³, —NR¹⁹⁴C(═O)NR¹⁹⁴C(═O)R¹⁹⁰,NR¹⁹⁴C(═O)NR¹⁹⁴C(═O)OR¹⁹⁰, NR¹⁹⁴C(═NR¹⁹⁵)NR¹⁹²R¹⁹³,—NR¹⁹⁴C(═O)C(═O)NR¹⁹²R¹⁹³, —NR¹⁹⁴C(═S)R¹⁹⁰, NR¹⁹⁴C(═S)OR¹⁹⁰,NR¹⁹⁴C(═S)NR¹⁹²R¹⁹³, —NR¹⁹⁴S(═O)₂R¹⁹, NR¹⁹⁴S(═O)₂NR¹⁹²R¹⁹,NR¹⁹⁴P(═O)R¹⁹⁸R¹⁹⁸, —NR¹⁹⁴P(═ONR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³),—NR¹⁹⁴P(═)(OR¹⁹⁰)(OR¹⁹⁰), —NR¹⁹⁴P(═O)(SR¹⁹⁰)(SR¹⁹⁰), —OR¹⁹⁰, ═O, —OCN,—OC(═O)R¹⁹⁰, —OC(═O)NR¹⁹²R¹⁹³, —OC(═O)OR¹⁹⁰, —OC(═NR¹⁹⁵)NR¹⁹²R¹⁹³,—OS(═O)R¹⁹⁰, —OS(═O)₂R¹⁹⁰, —OS(═O)₂OR¹⁹⁰, —OS(═O)₂NR¹⁹²R¹⁹³,—OP(═O)R¹⁹⁸R¹⁹⁸, —OP(═O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³), —OP(═O)(OR¹⁹⁰)(OR¹⁹⁰),—OP(═O)(SR¹⁹⁰)(SR¹⁹⁰), —Si(R¹⁹⁴)₃, —SCN, ═S, —S(═O)_(n)R¹⁹⁰,—S(═O)₂OR¹⁹⁰, —SO₃R, —S(═O)₂NR¹⁹²R¹⁹³, —S(═O)NR¹⁹²R¹⁹³, —SP(═O)R¹⁹⁸R¹⁹⁸,—SP(═O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³), —SP(═O)(OR¹⁹⁰)(OR¹⁹⁰),—SP(═O)(SR¹⁹⁰)(SR¹⁹⁰), —P(═O)R¹⁹⁸R¹⁹⁸, —P(═O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³),—P(═O)(OR¹⁹⁰)(OR¹⁹⁰), and —P(═O)(SR¹⁹⁰)(SR¹⁹⁰).

Embodiment 1003

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R¹⁹⁹, C₆₋₁₁aryloptionally substituted by 1-6 R¹⁹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-6 R¹⁹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R¹⁹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹⁹,5-15 membered heteroaryl optionally substituted by 1-6 R¹⁹⁹, halogen,—CN, —C(═O)R¹⁹⁰, —C(═O)OR¹⁹⁰, —C(═O)NR¹⁹²R¹⁹³, —NC, —NO₂, —NR¹⁹²R¹⁹³,—NR¹⁹⁴NR¹⁹²R¹⁹³, —NR¹⁹⁴OR¹⁹⁶, —NR¹⁹⁴C(═O)R¹⁹⁰, —NR¹⁹⁴C(═O)OR¹⁹¹,—NR¹⁹⁴C(═O)NR¹⁹²R¹⁹³, —NR¹⁹⁴C(═O)NR¹⁹⁴C(═O)R¹⁹⁰, —NR¹⁹⁴S(═O)₂R¹⁹¹,—NR¹⁹⁴S(═O)₂NR¹⁹²R¹⁹³, —OR¹⁹⁰, ═O, —OCN, —OC(═O)R¹⁹⁰, —OC(═O)NR¹⁹²R¹⁹³,—OC(═O)OR¹⁹⁰, —Si(R¹⁹⁴)₃, —SCN, ═S, —S(═O)_(n)R¹⁹⁰, and—S(═O)₂NR¹⁹²R¹⁹³.

Embodiment 1004

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R¹⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 R¹⁹⁹, C₆₋₁₀aryloptionally substituted by 1-6 R¹⁹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-6 R¹⁹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6R¹⁹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-6 R¹⁹⁹,5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹⁹, halogen,—CN, —C(═O)R¹⁹⁰, —C(═O)OR¹⁹⁰, —C(═O)NR¹⁹²R¹⁹³, —NO₂, —NR¹⁹²R¹⁹³,—NR¹⁹⁴C(═O)R¹⁹⁰, NR¹⁹⁴C(═O)OR, —NR¹⁹⁴C(═O)NR¹⁹²R¹⁹³,—NR¹⁹⁴C(═O)NR¹⁹⁴C(═O)R¹⁹⁰, —NR¹⁹⁴S(═O)₂R¹⁹¹, —NR¹⁹⁴S(═O)₂NR¹⁹²R¹⁹³,—OR¹⁹⁰, ═O, —OC(═O)R¹⁹⁰, —OC(═O)NR¹⁹²R¹⁹³, —OC(═O)OR¹⁹⁰, —Si(R¹⁹⁴)₃,—S(═O)_(n)R¹⁹⁰, and —S(═O)₂NR¹⁹²R¹⁹³.

Embodiment 1005

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹⁹, C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-3 R¹⁹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R¹⁹⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹⁹,5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹⁹, halogen,—CN, —C(═O)R¹⁹⁰, —C(═O)OR¹⁹⁰, —C(═O)NR¹⁹²R¹⁹³, —NO₂, —NR¹⁹²R¹⁹³,—NR¹⁹⁴C(═O)R¹⁹⁰, NR¹⁹⁴C(═O)OR¹⁹¹, —NR¹⁹⁴C(═O)NR¹⁹²R¹⁹³,—NR¹⁹⁴C(═O)NR¹⁹⁴C(═O)R¹⁹⁰, —NR¹⁹⁴S(═O)₂R¹⁹¹, —NR¹⁹⁴S(═O)₂NR¹⁹²R¹⁹³,—OR¹⁹⁰, ═O, —OC(═O)R¹⁹⁰, —OC(═O)NR¹⁹²R¹⁹³, —OC(═O)OR¹⁹⁰, —Si(R¹⁹⁴)₃,—S(═O)_(n)R¹⁹⁰, and —S(═O)₂NR¹⁹²R¹⁹³.

Embodiment 1006

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹⁹, phenyloptionally substituted by 1-3 R¹⁹⁹, benzyl optionally substituted by 1-3R¹⁹⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹⁹, halogen, —CN, —C(═O)R¹⁹⁰,—C(═O)OR¹⁹⁰, —C(═O)NR¹⁹²R¹⁹³, —NO₂, —NR¹⁹²R¹⁹³, —NR¹⁹⁴C(═O)R¹⁹⁰,—NR¹⁹⁴C(═O)OR¹⁹¹, —NR¹⁹⁴C(═O)NR¹⁹²R¹⁹³, —NR¹⁹⁴C(═O)NR¹⁹⁴C(═O)R¹⁹⁰,—NR¹⁹⁴S(═O)₂R¹⁹¹, —NR¹⁹⁴S(═O)₂NR¹⁹²R¹⁹³, —OR¹⁹⁰, ═O, —OC(═O)R¹⁹⁰,—OC(═O)NR¹⁹²R, —OC(═O)OR¹⁹⁰, Si(R¹⁹⁴)₃, —S(═O)_(n)R¹⁹⁰, and—S(═O)₂NR¹⁹²R¹⁹³.

Embodiment 1007

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹⁹, phenyloptionally substituted by 1-3 R¹⁹⁹, benzyl optionally substituted by 1-3R¹⁹⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹⁹, halogen, —CN, —C(═O)R¹⁹⁰,—C(═O)OR¹⁹⁰, —C(═O)NR¹⁹²R¹⁹³, —NO₂, —NR¹⁹²R¹⁹³, —NR¹⁹⁴C(═O)R¹⁹⁰,—NR¹⁹⁴S(═O)₂R¹⁹¹, —OR¹⁹⁰, —OC(═O)R¹⁹⁰, —OC(═O)NR¹⁹²R¹⁹³, —S(═O)_(n)R¹⁹⁰,and —S(═O)₂NR¹⁹²R¹⁹³.

Embodiment 1008

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl, phenyl, benzyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R¹⁹⁰,—C(═O)OR¹⁹⁰, —C(═O)NR¹⁹²R⁹, —NO₂, —NR¹⁹²R¹⁹³, —NR¹⁹⁴C(═O)R¹⁹⁰,—NR¹⁹⁴S(═O)₂R¹⁹¹, —OR¹⁹⁰, —OC(═O)R¹⁹⁰, —OC(═O)NR¹⁹²R¹⁹³, —S(═O)_(n)R¹⁹⁰,and —S(═O)₂NR¹⁹²R¹⁹³.

Embodiment 1009

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl, phenyl, benzyl, halogen, —CN, —C(═O)OR¹⁹⁰,—C(═O)NR¹⁹²R¹⁹³, —NO₂, —NR¹⁹²R¹⁹³, —OR¹⁹⁰, and —S(═O)_(n)R¹⁹⁰.

Embodiment 1010

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹⁹, phenyloptionally substituted by 1-3 R¹⁹⁹, benzyl optionally substituted by 1-3R¹⁹⁹, halogen, —CN, —C(═O)OR¹⁹⁰, —C(═O)NR¹⁹²R¹⁹³, —NO₂, —NR¹⁹²R¹⁹³,—OR¹⁹⁰, and —S(═O)_(n)R¹⁹⁰.

Embodiment 1011

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R¹⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl, phenyl, benzyl, halogen, —NR¹⁹²R¹⁹³, and —OR¹⁹⁰.

Embodiment 1012

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl, halogen, —NR¹⁹²R¹⁹³, and —OR¹⁹⁰.

Embodiment 1013

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹⁹ and halogen.

Embodiment 1014

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 R¹⁹⁹

Embodiment 1015

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1001,wherein R⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independentlyC₁₋₆alkyl.

Embodiment 1016

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R²⁰⁹, C₂₋₆alkenyl optionally substituted by 1-11 R²⁰⁹, C₂₋₆alkynyloptionally substituted by 1-9 R²⁰⁹, C₆-11aryl optionally substituted by1-11 R²⁰⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R²⁰⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R²⁰⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R²⁰⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R²⁰⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R²⁰⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R²⁰⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R²⁰⁹

Embodiment 1017

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-6R²⁰⁹, C₂₋₆alkenyl optionally substituted by 1-6 R²⁰⁹, C₂₋₆alkynyloptionally substituted by 1-6 R²⁰⁹, C₆₋₁₀aryl optionally substituted by1-6 R²⁰⁹, C₇₋₁₁arylalkyl optionally substituted by 1-6 R²⁰⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-6 R²⁰⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-6 R²⁰⁹, and 5-10 memberedheteroaryl optionally substituted by 1-6 R²⁰⁹

Embodiment 1018

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R²⁰⁹, C₂₋₆alkenyl optionally substituted by 1-3 R²⁰⁹, C₂₋₆alkynyloptionally substituted by 1-3 R²⁰⁹, C₆₋₁₀aryl optionally substituted by1-3 R²⁰⁹, C₇₋₁₁-arylalkyl optionally substituted by 1-3 R²⁰⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R²⁰⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R²⁰⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R²⁰⁹

Embodiment 1019

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R²⁰⁹, phenyl optionally substituted by 1-3 R²⁰⁹, benzyl optionallysubstituted by 1-3 R²⁰⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R²⁰⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R²⁰⁹,and 5-10 membered heteroaryl optionally substituted by 1-3 R²⁰⁹.

Embodiment 1020

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl, benzyl, C₃₋₁₀cycloalkyl,3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

Embodiment 1021

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R²⁰⁹, phenyl optionally substituted by 1-3 R²⁰⁹, benzyl optionallysubstituted by 1-3 R²⁰⁹, C₅₋₆cycloalkyl optionally substituted by 1-3R²⁰⁹, 5-6 membered heterocycloalkyl optionally substituted by 1-3 R²⁰⁹,and 5-6 membered heteroaryl optionally substituted by 1-3 R²⁰⁹

Embodiment 1022

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl,5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 1023

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl, C₅₋₆cycloalkyl, 5-6membered heterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 1024

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl,5-6 membered heterocycloalkyl optionally substituted by 1 R²⁰⁹, and 5-6membered heteroaryl.

Embodiment 1025

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl optionally substituted by 1-3R²⁰⁹.

Embodiment 1026

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence isindependently chosen from H and C₁₋₆alkyl.

Embodiment 1027

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1015,wherein R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence is H.

Embodiment 1028

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-13 R²¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-11 R²¹⁹, C₂₋₆alkynyl optionally substituted by 1-9R²¹⁹, C₆₋₁₁aryl optionally substituted by 1-11 R²¹⁹, C₇₋₁₆arylalkyloptionally substituted by 1-19 R²¹⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-21 R²¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by1-32 R²¹⁹, 3-15 membered heterocycloalkyl optionally substituted by 1-28R²¹⁹, 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40R²¹⁹, 5-15 membered heteroaryl optionally substituted by 1-15 R²¹⁹, and6-21 membered heteroarylalkyl optionally substituted by 1-27 R²¹⁹; orany R¹⁹² and R¹⁹³ may form, together with the nitrogen atom to whichthey are attached, a 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R²²⁹ or a 5-15 membered heteroaryl optionallysubstituted by 1-15 R²²⁹.

Embodiment 1029

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-6 R²¹⁹, C₂₋₆alkenyl optionallysubstituted by 1-6 R²¹⁹, C₂₋₆alkynyl optionally substituted by 1-6 R²¹⁹,C₆₋₁₁aryl optionally substituted by 1-6 R²¹⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-6 R²¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-6R²¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-6 R²¹⁹, 3-15membered heterocycloalkyl optionally substituted by 1-6 R²¹⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-6 R²¹⁹, 5-15membered heteroaryl optionally substituted by 1-6 R²¹⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-6 R²¹⁹; or any R¹⁹²and R¹⁹³ may form, together with the nitrogen atom to which they areattached, a 3-15 membered heterocycloalkyl optionally substituted by 1-6R²²⁹ or a 5-15 membered heteroaryl optionally substituted by 1-6 R²²⁹.

Embodiment 1030

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R²¹⁹, phenyl optionallysubstituted by 1-3 R²¹⁹, benzyl optionally substituted by 1-3 R²¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R²¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R²¹⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R²¹⁹; or any R¹⁹² and R¹⁹³ mayform, together with the nitrogen atom to which they are attached, a 3-15membered heterocycloalkyl optionally substituted by 1-3 R²²⁹ or a 5-15membered heteroaryl optionally substituted by 1-3 R²²⁹.

Embodiment 1031

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R²¹⁹, phenyl optionallysubstituted by 1-3 R²¹⁹, benzyl optionally substituted by 1-3 R²¹⁹,C₃₋₁₀cycloalkyl optionally substituted by 1-3 R²¹⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R²¹⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R²¹⁹.

Embodiment 1032

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R²¹⁹, phenyl optionallysubstituted by 1-3 R²¹⁹, benzyl optionally substituted by 1-3 R²¹⁹,C₃₋₆cycloalkyl optionally substituted by 1-3 R²¹⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R²¹⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R²¹⁹; or any R¹⁹² and R¹⁹³ mayform, together with the nitrogen atom to which they are attached, a 3-10membered heterocycloalkyl optionally substituted by 1-3 R²²⁹ or a 5-10membered heteroaryl optionally substituted by 1-3 R²²⁹.

Embodiment 1033

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R²¹⁹, phenyl optionallysubstituted by 1-3 R²¹⁹, benzyl optionally substituted by 1-3 R²¹⁹,C₅₋₆cycloalkyl optionally substituted by 1-3 R²¹⁹, 5-6 memberedheterocycloalkyl optionally substituted by 1-3 R²¹⁹, and 5-6 memberedheteroaryl optionally substituted by 1-3 R²¹⁹.

Embodiment 1034

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R²¹⁹, phenyl optionallysubstituted by 1-3 R²¹⁹, benzyl optionally substituted by 1-3 R²¹⁹, 5-6membered heterocycloalkyl optionally substituted by 1-3 R²¹⁹, and 5-6membered heteroaryl optionally substituted by 1-3 R²¹⁹.

Embodiment 1035

The compound of any of Embodiments 1-156, 200-250, 300-371,

400-440, 500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or900-1027, wherein R¹⁹² and R¹⁹³ at each occurrence is independentlychosen from H, C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl; or any R¹⁹² and R¹⁹³ mayform, together with the nitrogen atom to which they are attached, a 5-6membered heterocycloalkyl or a 5-6 membered heteroaryl.

Embodiment 1036

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, benzyl, C₅₋₆cycloalkyl, 5-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl.

Embodiment 1037

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R²¹⁹, phenyl optionallysubstituted by 1-3 R²¹⁹, and benzyl optionally substituted by 1-3 R²¹⁹.

Embodiment 1038

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from Hand C₁₋₆alkyl optionally substituted by 1-3 R²¹⁹.

Embodiment 1039

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,C₁₋₆alkyl, phenyl, and benzyl.

Embodiment 1040

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is independently chosen from Hand C₁₋₆alkyl.

Embodiment 1041

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1027,wherein R¹⁹² and R¹⁹³ at each occurrence is H.

Embodiment 1042

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041,wherein R¹⁹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-13 R²⁰⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R²⁰⁹, C₂₋₆alkynyl optionally substituted by 1-9 R²⁰⁹, C₆₋₁₁aryloptionally substituted by 1-11 R²⁰⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R²⁰⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R²⁰⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R²⁰⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R²⁰⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R²⁰⁹, 5-15membered heteroaryl optionally substituted by 1-15 R²⁰⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R²⁰⁹.

Embodiment 1043

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041,wherein R¹⁹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R²⁰⁹, C₂₋₆alkenyl optionally substitutedby 1-3 R²⁰⁹, C₂₋₆alkynyl optionally substituted by 1-3 R²⁰⁹, C₆₋₁₁aryloptionally substituted by 1-3 R²⁰⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-3 R²⁰⁹, C₃ 11cycloalkyl optionally substituted by 1-3R²⁰⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-3 R²⁰⁹, 3-15membered heterocycloalkyl optionally substituted by 1-3 R²⁰⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-3 R²⁰⁹, 5-15membered heteroaryl optionally substituted by 1-3 R²⁰⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-3 R²⁰⁹.

Embodiment 1044

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041,wherein R¹⁹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R²⁰⁹, C₂₋₆alkenyl optionally substitutedby 1-3 R²⁰⁹, C₂₋₆alkynyl optionally substituted by 1-3 R²⁰⁹, C₆₋₁₀aryloptionally substituted by 1-3 R²⁰⁹, C₇₋₁₁arylalkyl optionallysubstituted by 1-3 R²⁰⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3R²⁰⁹, 3-10 membered heterocycloalkyl optionally substituted by 1-3 R²⁰⁹,and 5-10 membered heteroaryl optionally substituted by 1-3 R²⁰⁹.

Embodiment 1045

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041,wherein R¹⁹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R²⁰⁹, C₆₋₁₀aryl optionally substituted by1-3 R²⁰⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3 R²⁰⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-3 R²⁰⁹, 3-10 memberedheterocycloalkyl optionally substituted by 1-3 R²⁰⁹, and 5-10 memberedheteroaryl optionally substituted by 1-3 R²⁰⁹.

Embodiment 1046

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041,wherein R¹⁹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R²⁰⁹, phenyl optionally substituted by 1-3R²⁰⁹, benzyl optionally substituted by 1-3 R²⁰⁹, C₃-6cycloalkyloptionally substituted by 1-3 R²⁰⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R²⁰⁹, and 5-6 membered heteroaryloptionally substituted by 1-3 R²⁰⁹

Embodiment 1047

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041,wherein R¹⁹⁸ at each occurrence is independently chosen from C₁₋₆alkyl,phenyl, benzyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6membered heteroaryl.

Embodiment 1048

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041,wherein R¹⁹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R²⁰⁹, phenyl, and benzyl.

Embodiment 1049

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041,wherein R¹⁹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-3 R²⁰⁹, phenyl optionally substituted by 1-3R²⁰⁹, and benzyl optionally substituted by 1-3 R²⁰⁹.

Embodiment 1050

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041,wherein R¹⁹⁸ at each occurrence is independently chosen from C₁₋₆alkyl,phenyl, and benzyl.

Embodiment 1051

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041,wherein R¹⁹⁸ at each occurrence is C₁₋₆alkyl optionally substituted by1-3 R²⁰⁹

Embodiment 1052

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1041,wherein R¹⁹⁸ at each occurrence is C₁₋₆alkyl.

Embodiment 1053

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-13 halogen,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₁aryl, C₇₋₁₆arylalkyl, C₃₋₁₁cycloalkyl,C₄₋₁₇cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 memberedheterocycloalkylalkyl, 5-15 membered heteroaryl, 6-21 memberedheteroarylalkyl, halogen, —CN, —C(═O)R²³⁰, —C(═O)OR²³⁰, —C(═O)NR²³⁰R²³⁰,—C(═O)C(═O)R²³⁰, —C(═NR²³⁰)R²³⁰, —C(═NR²³⁰)NR²³⁰R²³⁰, —C(═NOH)NR²³⁰R²³⁰,—C(═NOR²³⁰)R²³⁰, —C(═NNR²³⁰R²³⁰)R²³⁰, —C(═NNR²³⁰C(═O)R²³⁰)R²³⁰,—C(═NNR²³⁰C(═O)OR²³⁰)R²³⁰, —C(═S)NR²³⁰R²³⁰, —NC, —NO₂, —NR²³⁰R²³⁰,—NR²³⁰NR²³⁰R²³⁰, —N═NR²³⁰, ═NR²³⁰, ═NOR²³⁰, —NR²³⁰OR²³⁰,—NR²³⁰C(═O)R²³⁰, —NR²³⁰C(═O)C(═O)R²³⁰, —NR²³⁰C(═O)OR²³⁰,—NR²³⁰C(═O)C(═O)OR²³⁰, —NR²³⁰C(═O)NR²³⁰R²³⁰, —NR²³⁰C(═O)NR²³⁰C(═O)R²³⁰,—NR²³⁰C(═O)NR²³⁰C(═O)OR²³⁰, —NR²³⁰C(═NR²³⁰)NR²³⁰R²³⁰,—NR²³⁰C(O)C(═O)NR²³⁰R²³⁰, —NR²³⁰C(═S)R²³⁰, —NR²³⁰C(═S)OR²³⁰,—NR²³⁰C(═S)NR²³⁰R²³⁰, —NR²³⁰S(═O)₂R²³⁰, —NR²³⁰S(═O)₂N²³⁰R²³⁰,NR²³⁰P(═O)R²³¹R²³¹, —NR²³⁰P(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰),—NR²³⁰P(═O)(OR²³⁰)(OR²³⁰), —NR²³⁰P(═)(SR²³⁰)(SR²³⁰), —OR²³⁰, ═O, —OCN,—OC(═O)R²³⁰, OC(═O)NR²³⁰R²³⁰, —OC(═)OR²³⁰, —OC(═NR²³⁰)NR²³⁰R²³⁰,—OS(═O)R²³⁰, —OS(═O)₂R²³⁰, —OS(═O)₂OR²³⁰, OS(═O)₂NR²³⁰R²³⁰,—OP(═O)R²³¹R²³¹, —OP(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰), —OP(═)(OR²³⁰)(OR²³⁰),—OP(═O)(SR²³⁰)(SR²³⁰), —Si(R²³⁰)₃, —SCN, ═S, —S(═O)_(n)R²³⁰,—S(═O)₂R²³⁰, —SO₃R²³⁰, —S(═O)₂NR²³⁰R²³⁰, —S(═O)NR²³⁰R²³⁰,—SP(═O)R²³¹R²³¹, —SP(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰), —SP(═O)(OR²³⁰)(OR²³⁰),—SP(═O)(SR²³⁰)(SR²³⁰), —P(═O)R²³¹R²³¹, —P(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰),—P(═O)(OR²³⁰)(OR²³⁰), and —P(═O)(SR²³⁰)(SR²³⁰).

Embodiment 1054

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-6 halogen,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₁aryl, C₇₋₁₆arylalkyl, C₃₋₁₁cycloalkyl,C₄₋₁₇cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-15 memberedheterocycloalkylalkyl, 5-15 membered heteroaryl, 6-15 memberedheteroarylalkyl, halogen, —CN, —C(═O)R²³⁰, —C(═O)OR²³⁰, —C(═O)NR²³⁰R²³⁰,—C(═O)C(═O)R²³⁰, —NC, —NO₂, —NR²³⁰R²³⁰, NR²³⁰NR²³⁰R²³⁰, NR²³⁰OR²³⁰,—NR²³⁰C(═O)R²³⁰, —NR²³⁰C(═O)C(═O)R²³⁰, —NR²³⁰C(═O)OR²³⁰,—NR²³⁰C(═O)C(═O)OR²³⁰, —NR²³⁰C(═O)NR²³⁰R²³⁰, —NR²³⁰C(═O)NR²³⁰C(═O)R²³⁰,—NR²³⁰C(═O)NR²³⁰C(═O)OR²³⁰, —NR²³⁰C(═O)C(═O)NR²³⁰R²³⁰, —NR²³⁰S(═O)₂R²³⁰,NR²³⁰S(═O)₂NR²³⁰R²³⁰, NR²³⁰P(═O)R²³¹R²³¹,—NR²³⁰P(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰), —NR²³⁰P(═O)(OR²³⁰)(OR²³⁰), —OR²³⁰,═O, —OCN, —OC(═O)R²³⁰, —OC(═O)NR²³⁰R²³⁰, —OC(═O)OR²³⁰, —OS(═O)R²³⁰,—OS(═O)₂R²³⁰, —OS(═O)₂R²³⁰, —OS(═O)₂NR²³⁰R²³⁰, —OP(═O)R²³¹R²³¹,—OP(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰), —OP(═O)(OR²³⁰)(OR²³⁰), —Si(R²³⁰)₃, —SCN,═S, —S(═O)_(n)R²³⁰, —S(═O)₂OR²³⁰, —SO₃R²³⁰, —S(═O)₂NR²³⁰R²³⁰,—S(═O)NR²³⁰R²³⁰, —P(═O)R²³¹R²³¹, —P(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰), and—P(═O)(OR²³⁰)(OR²³⁰).

Embodiment 1055

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 halogen,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆ ¹⁰aryl, C₇₋₁₁arylalkyl, C₃₋₁₀cycloalkyl,C₄₋₁₇cycloalkylalkyl, 3-10 membered heterocycloalkyl, 4-10 memberedheterocycloalkylalkyl, 5-10 membered heteroaryl, 6-10 memberedheteroarylalkyl, halogen, —CN, —C(═O)R²³⁰, —C(═O)OR²³⁰, —C(═O)NR²³⁰R²³⁰,—NC, —NO₂, —NR²³⁰R²³⁰, —NR²³⁰OR²³⁰, —NR²³⁰C(═O)R²³⁰, —NR²³⁰C(═O)OR²³⁰,—NR²³⁰C(═O)NR²³⁰R²³⁰, —NR²³⁰C(═O)NR²³⁰C(═O)R²³⁰, —NR²³⁰S(═O)₂R²³⁰,—NR²³⁰S(═O)₂NR²³⁰R²³⁰, NR²³⁰P(═O)R²³¹R²³¹,NR²³⁰P(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰), —NR²³⁰P(═O)(OR²³⁰)(OR²³⁰), —OR²³⁰, ═O,—OCN, —OC(═O)R²³⁰, —OC(═O)NR²³⁰R²³⁰, —OS(═O)₂NR²³⁰R²³⁰, —OP(═O)R²³¹R²³¹,—OP(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰), —SCN, ═S, —S(═O)_(n)R²³⁰,—S(═O)₂NR²³⁰²³⁰, —S(═O)NR²³⁰R²³⁰, —P(═O)R²³¹R²³¹, and—P(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰).

Embodiment 1056

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 halogen,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆10aryl, C₇₋₁₁arylalkyl, C₃₋₁₀cycloalkyl,3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN,—C(═O)R²³⁰, —C(═O)OR²³⁰, —C(═O)NR²³⁰R²³⁰, —NO₂, —NR²³⁰R²³⁰, —NR²³⁰OR²³⁰,—NR²³⁰C(═O)R²³⁰, —NR²³⁰C(═O)NR²³⁰R²³⁰, —NR²³⁰S(═O)₂R²³⁰,—NR²³⁰S(═O)₂NR²³⁰R²³⁰, —OR²³⁰, ═O, —OCN, —OC(═O)R²³⁰, —S(═O)_(n)R²³⁰,S(═O)₂NR²³⁰R²³⁰, and —S(═O)NR²³⁰R²³⁰.

Embodiment 1057

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 halogen,C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl, benzyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R²³⁰,—C(═O)OR²³⁰, —C(═O)NR²³⁰R²³⁰, —NO₂, —NR²³⁰R²³⁰, —NR²³⁰C(═O)R²³⁰,—NR²³⁰C(═O)NR²³⁰R²³⁰, —NR²³⁰S(═O)₂R²³⁰, —NR²³⁰S(═O)₂NR²³⁰R²³⁰, —OR²³⁰,═O, —S(═O)_(n)R²³⁰, and —S(═O)₂NR²³⁰R²³⁰.

Embodiment 1058

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 halogen,C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl, benzyl, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl, 5-6 membered heteroaryl, halogen, —CN, —C(═O)R²³⁰,—C(═O)OR²³⁰, —C(═O)NR²³⁰R²³⁰, —NR²³⁰R²³⁰, —NR²³⁰C(═O)R²³⁰,—NR²³⁰S(═O)₂R²³⁰, —OR²³⁰, ═O, —S(═O)_(n)R²³⁰, and —S(═O)₂NR²³⁰R²³⁰.

Embodiment 1059

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 halogen, phenyl,benzyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 memberedheteroaryl, halogen, —CN, —C(═O)R²³⁰, —C(═O)OR²³⁰, —C(═O)NR²³⁰R²³⁰,NR²³⁰R²³⁰, —OR²³⁰, ═O, —S(═O)_(n)R²³⁰, and —S(═O)₂NR²³⁰R²³⁰.

Embodiment 1060

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independentlychosen from C₁₋₆alkyl optionally substituted by 1-3 halogen, halogen,and —NR²30R²³⁰

Embodiment 1061

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independentlychosen from C₁₋₆alkyl, halogen, and —NR²³⁰R²³⁰.

Embodiment 1062

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independentlychosen from C₁₋₆alkyl and —NR²³⁰R²³⁰

Embodiment 1063

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is —NR²³⁰R²³⁰.

Embodiment 1064

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is C₁₋₆alkyl.

Embodiment 1065

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹ at each occurrence is independently chosen from C₁₋₆alkyland —NR²³⁰R²³⁰; R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is C₁₋₆alkyl.

Embodiment 1066

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹ at each occurrence is independently chosen from C₁₋₆alkyland —NR²³⁰R²³⁰; R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is —NR²³⁰R²³⁰.

Embodiment 1067

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1052,wherein R¹⁹⁹ at each occurrence is —NR²³⁰R²³⁰; R²⁰⁹, R²¹⁹ and R²²⁹ ateach occurrence is C₁₋₆alkyl.

Embodiment 1068

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1067,wherein R²³⁰ at each occurrence is independently chosen from H,C₁₋₆alkyl and C₁₋₆-haloalkyl.

Embodiment 1069

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1067,wherein R²³⁰ at each occurrence is independently chosen from H andC₁₋₆alkyl.

Embodiment 1070

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1067,wherein R²³⁰ at each occurrence is C₁₋₆alkyl.

Embodiment 1071

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1067,wherein R²³⁰ at each occurrence is H.

Embodiment 1072

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1071,wherein R²³¹ at each occurrence is independently chosen from C₁₋₆alkyland C₁₋₆-haloalkyl.

Embodiment 1073

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1071,wherein R²³¹ at each occurrence is C₁₋₆alkyl.

Embodiment 1074

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1071,wherein R²³¹ at each occurrence is C₁₋₆-haloalkyl.

Embodiment 1075

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074,wherein n at each occurrence is independently chosen from 0, 1, and 2.

Embodiment 1076

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074,wherein n at each occurrence is independently chosen from 0 and 2.

Embodiment 1077

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074,wherein n at each occurrence is independently chosen from 1 and 2.

Embodiment 1078

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074,wherein n at each occurrence is independently chosen from 0 and 1.

Embodiment 1079

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074,wherein n at each occurrence is O.

Embodiment 1080

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074,wherein n at each occurrence is 1.

Embodiment 1081

The compound of any of Embodiments 1-156, 200-250, 300-371, 400-440,500-533, 600-668, 700-714, 750-795, 800-817, 850-886, or 900-1074,wherein n at each occurrence is 2.

The above Embodiments include salts of acidic and basic compounds offormula (I). Preferably, the salts are pharmaceutically acceptable.Pharmaceutically acceptable acid addition salts of basic compounds offormula (I) include, but are not limited to, salts derived frominorganic acids such as hydrochloric, nitric, phosphoric, sulfuric,hydrobromic, hydriodic, and phosphorus, as well as the salts derivedfrom organic acids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Suchsalts thus include, but are not limited to, sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,caprylate, isobutyrate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate,methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate,toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate,and methanesulfonate. See, for example, Berge et al., “PharmaceuticalSalts,” J. of Pharmaceutical Science, 1977; 66:1-19.

Acid addition salts may be prepared by contacting a compound of formula(I) with a sufficient amount of the desired acid to produce the salt inthe conventional manner. The free base form of the compound of formula(I) may be regenerated by contacting the salt form with a base andisolating the free base in the conventional manner.

Pharmaceutically acceptable base salts of acidic compounds of formula(I) are formed with metals or amines, such as alkali and alkaline earthmetal hydroxides, or of organic amines.

Examples of metals used as cations include, but are not limited to,sodium, potassium, magnesium, and calcium. Examples of suitable aminesinclude, but are not limited to, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine(ethane-1,2-diamine), N-methylglucamine, and procaine. See, for example,Berge et al., “Pharmaceutical Salts,” J. of Pharmaceutical Science,1977; 66:1-19.

Base salts may be prepared by contacting a compound of formula (I) witha sufficient amount of the desired base to produce the salt in theconventional manner. The acid form of the compound of formula (I) may beregenerated by contacting the salt form with an acid and isolating theacid in a conventional manner.

Some compounds of the present application may exist as stereoisomers,including enantiomers, diastereomers, and geometric isomers. Geometricisomers include compounds of the present application that have alkenylgroups, which may exist as entgegen or zusammen conformations, in whichcase all geometric forms thereof, both entgegen and zusammen, cis andtrans, and mixtures thereof, are within the scope of the presentapplication. Some compounds of the present application have cycloalkylgroups, which may be substituted at more than one carbon atom, in whichcase all geometric forms thereof, both cis and trans, and mixturesthereof, are within the scope of the present application. All of theseforms, including (R), (S), epimers, diastereomers, cis, trans, syn,anti, (E), (Z), tautomers, and mixtures thereof, are included in thecompounds of the present application.

The compounds of the present application may be in any physical form,including amorphous or crystalline solids in any polymorphic form, inany state of purity. Crystalline polymorphic forms include unsolvatedforms as well as solvated forms, such as hydrated forms.

III. Pharmaceutical Compositions

The present application further provides pharmaceutical compositionscomprising a compound of any of the above Embodiments (e.g., a compoundof formula (I) or a pharmaceutically acceptable salt thereof), togetherwith a pharmaceutically acceptable excipient.

For preparing a pharmaceutical composition from a compound of thepresent application, pharmaceutically acceptable excipients can beeither solid or liquid. An excipient can be one or more substances whichmay act as, e.g., a carrier, diluent, flavoring agent, binder,preservative, tablet disintegrating agent, or an encapsulating material.The pharmaceutical composition may contain two or more compounds of thepresent application (e.g., two different salt forms of a compound offormula (I), may be used together in the same pharmaceuticalcomposition). Preferably, the pharmaceutical composition contains atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt form thereof. In one embodiment, thecomposition contains an amount of a compound of formula (I) or apharmaceutically acceptable salt form thereof effective to treat anatypical protein kinase C (aPKC)-dependent disorder or condition.Preferably, a compound of the present application will cause a decreasein symptoms or disease indicia associated with an aPKC-dependentdisorder as measured quantitatively or qualitatively. The compositionmay also contain, in addition to a compound of formula (I) or apharmaceutically acceptable salt form thereof and a pharmaceuticallyacceptable excipient, another therapeutic compound, such as a compounduseful in the treatment of cancer.

A compound of the present application can be formulated as apharmaceutical composition in any delivery form, such as a syrup, anelixir, a suspension, a powder, a granule, a tablet, a capsule, alozenge, a troche, an aqueous solution, a cream, an ointment, a lotion,a gel, an emulsion, etc. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. Preferably, the pharmaceutical composition is a tablet orcapsule. In one embodiment, the pharmaceutical composition is a tablet.In another embodiment, the pharmaceutical composition is a capsule.

In powders, the excipient may be a finely divided solid in a mixturewith a finely divided active component (i.e., compound of the presentapplication). In tablets, the active component may be mixed with anexcipient having the necessary binding properties in suitableproportions and compacted in the shape and size desired. Suitableexcipients include magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,sodium carboxymethylcellulose, low melting wax, cocoa butter, and thelike.

The pharmaceutical composition preferably contains from 1% to 95% (w/w)of the active compound (i.e., compound of the present application). Morepreferably, the pharmaceutical composition contains from 5% to 70% (w/w)of the active compound.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, may be melted and the activecomponent dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture may then be poured into convenient sized molds,allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions.Formulations suitable for parenteral administration, such as, forexample, by intravenous, intramuscular, intradermal, and subcutaneousroutes, include aqueous and non-aqueous, isotonic sterile injectionsolutions, which can contain antioxidants, buffers, bacteriostats, andsolutes that render the formulation isotonic with the blood of theintended recipient, and aqueous and nonaqueous sterile suspensions thatcan include suspending agents, solubilizers, thickening agents,stabilizers, and preservatives. In practice, compositions can beadministered, for example, by intravenous infusion, orally, topically,intraperitoneally, intravesically or intrathecally. The formulations ofcompounds can be presented in unit-dose or multi-dose sealed containers,such as ampoules and vials. Injection solutions and suspensions can beprepared from sterile powders, granules, and tablets of the kindpreviously described.

A compound of the present application, alone or in combination withother suitable components, can be made into aerosol formulations (e.g.,they can be “nebulized”) to be administered via inhalation. Aerosolformulations can be placed into pressurized acceptable propellants, suchas dichlorodifluoromethane, propane, nitrogen, and the like.

Pharmaceutically acceptable excipients are determined in part by theparticular composition being administered, as well as by the particularmethod used to administer the composition. Accordingly, there is a widevariety of suitable formulations of pharmaceutical compositions of thepresent application (see, e.g., Remington: The Science and Practice ofPharmacy, 20th ed., Gennaro et al. Eds., Lippincott Williams andWilkins, 2000).

The quantity of active component in a pharmaceutical composition may bevaried or adjusted from, e.g., 1 mg to 1,000 mg, 5 mg to 500 mg, 10 mgto 300 mg, or 25 mg to 250 mg, according to the particular applicationand the desired size of the dosage form.

The dose administered to a subject is preferably sufficient to induce abeneficial therapeutic response in the subject over time. The beneficialdose can vary from subject to subject depending upon, e.g., thesubject's condition, body weight, surface area, and side effectsusceptibility. Administration can be accomplished via single or divideddoses.

IV. Method of Treatment

In another aspect, the present application provides a method of treatingan aPKC-dependent disorder or condition in a subject comprising:administering to the subject a compound of formula (I) as defined in anyof the above Embodiments or a pharmaceutically acceptable salt formthereof. In another aspect, the present application provides a compoundof formula (I) as defined in any of the above Embodiments or apharmaceutically acceptable salt form thereof for use in treating anaPKC-dependent disorder or condition in a subject. In another aspect,the present application provides a compound of formula (I) as defined inany of the above Embodiments or a pharmaceutically acceptable salt formthereof for use in the preparation of a medicament for treating anaPKC-dependent disorder or condition in a subject. Preferably, thecompound is administered to the subject as a pharmaceutical compositioncomprising a pharmaceutically acceptable excipient. Preferably, thecompound is administered to the subject in a pharmaceutically acceptableamount. In one embodiment, the aPKC-dependent condition or disorder iscancer. In another embodiment, the aPKC-dependent condition is selectedfrom non-small cell lung cancer (NSCLC), squamous cell carcinoma (e.g.,oesophageal squamous cell carcinoma), leukaemia, prostate cancer,non-Hodgkin's lymphoma (e.g., follicular lymphoma), endometrial cancer,lung cancer and breast cancer.

The aPKC-dependent disorder or condition can be treatedprophylactically, acutely, or chronically using compounds of the presentapplication, depending on the nature of the disorder or condition.Typically, the subject in each of these methods is human, although othermammals can also benefit from the administration of a compound of thepresent application.

In another embodiment, the present application provides a method oftreating a proliferative disorder in a subject, comprising administeringto the subject a compound of formula (I) as defined in any of the aboveEmbodiments or a pharmaceutically acceptable salt form thereof.

In another aspect, the present application provides a compound offormula (I) as defined in any of the above Embodiments or apharmaceutically acceptable salt form thereof for use in treating aproliferative disorder in a subject. In another aspect, the presentapplication provides a compound of formula (I) as defined in any of theabove Embodiments or a pharmaceutically acceptable salt form thereof foruse in the preparation of a medicament for treating a proliferativedisorder in a subject. Preferably, the compound is administered to thesubject in a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient. Preferably, the compound is administered to thesubject in a pharmaceutically acceptable amount. In certain embodiments,the proliferative disorder is aPKC-dependent. In certain embodiments,the proliferative disorder is cancer. In certain embodiments, theproliferative disorder is selected from non-small cell lung cancer(NSCLC), squamous cell carcinoma (e.g., oesophageal squamous cellcarcinoma), leukaemia, prostate cancer, non-Hodgkin's lymphoma (e.g.,follicular lymphoma), endometrial cancer, lung cancer and breast cancer.

The proliferative disorder can be treated prophylactically, acutely, orchronically using a compound of the present application, depending onthe nature of the disorder or condition. Typically, the subject in eachof these methods is human, although other mammals can also benefit fromthe administration of a compound of the present application.

In therapeutic applications, the compounds of the present applicationcan be prepared and administered in a wide variety of oral andparenteral dosage forms. Thus, the compounds of the present applicationcan be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally. Also, the compounds described herein can beadministered by inhalation, for example, intranasally. Additionally, thecompounds of the present application can be administered transdermally.In another embodiment, the compounds of the present application aredelivered orally. The compounds can also be delivered rectally, bucallyor by insufflation.

Determination of the proper dosage for a particular situation is withinthe skill of the practitioner. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day, if desired. A typical dose is about 1 mg to about 1,000 mg perday, such as about 5 mg to about 500 mg per day. In certain embodiments,the dose is about 10 mg to about 300 mg per day, such as about 25 mg toabout 250 mg per day.

V. Chemistry Abbreviations

For convenience, the following common abbreviations are used herein:

LCMS for Liquid Chromatography-Mass Spectrometry. HPLC for High PressureLiquid Chromatography. NMR for Nuclear Magnetic Resonance. RT forRetention Time. MI for Molecular Ion

h for hoursmin for minutesAlCl₃ for aluminium chlorideBBr₃ for boron tribromideBoc for tert-butoxycarbonylcataCXium C fortrans-Bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II).Cs₂CO₃ for cesium carbonateCuI for copper(I)iodideDAST for diethylaminosulfur trifluorideDBU for 1,8-diazabicyclo(5.4.0)undec-7-eneDMAP for 4-(dimethylamino) pyridineDCE for 1,1-dichloroethane or ethylidene chlorideDCM for dichloromethane or methylene chlorideDEA for diethanolamineDIPEA for N,N,-di-isopropyethylamine, Hunig's base

DMA for N,N-dimethylacetamide DMF for N,N-dimethylformamide

DMSO for dimethylsulfoxide.Et₃N for triethylamineEtOH for ethyl alcohol, ethanolEx for exampleHCl for hydrochloric acidH₂SO₄ for sulfuric acidInt for intermediateKOH for potassium hydroxideMW for microwavemCPBA for meta-Chloroperoxybenzoic acidMeOH for methyl alcohol, methanolMo(CO)₆ for Molybdenum hexacarbonylMP-BH₄ for macroporous triethylammonium methyl polystyrene borohydrideNaOH for sodium hydroxideNa₂CO₃ for sodium carbonateNa₂SO₄ for sodium sulphateNaOAc for sodium acetateNaOtBu for sodium t-butoxideNMP for 1-methyl-2-pyrrolidinone

NMM for N-methylmorpholine Pd(dba)₂ forBis(dibenzylideneacetone)palladium

Pd(OAc)₂ for Palladium diacetatePd(Ph₃)₄ for tetrakis(triphenylphosphine)palladiumPd(PPh₃)₂Cl₂ for Bis(triphenylphosphine)palladium(II) dichloridePOCl₃ for phosphorus oxychloridePPh₃ for triphenylphosphinePS-TsCl for polystyrene sulfonyl chloridePS-PPh₃-Pd for polystyrene triphenylphosphine-Pd(0)SCX-2 for a silica-based sorbent with a chemically bonded propylsulfonicacid functional groupTBAF for Tetra-n-butylammonium fluorideTBDMS for tert-butyldimethylsilylTCA for trichloroacetic acidTFA for trifluoroacetic acidTHF for tetrahydrofuranTMS azide for trimethylsilyl azideXantphos for 4,5-Bis(diphenylphosphino)-9,9-dimethylxantheneXPhos for 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

LCMS Methods

Samples analysed by High Performance Liquid Chromatography-MassSpectrometry employed the following conditions. Unless otherwise noted,Method X was utilized.

Method 1

Method 1 employed Gilson 306 pumps, Gilson 811C mixer, Gilson 806manometric module, and Gilson UV/VIS 152 detector at 254 nm wavelength.The mass spectrometer was a Finnigan AQA and the column used was aWaters SunFire, 5 μm pore size, C18 of dimensions 50×4.60 mm. Theinjection volume was 10 μl. The mobile phase consisted of a mixture ofwater and acetonitrile containing 0.1% formic acid. The eluent flow ratewas 1.5 mL/min, using 95% water: 5% acetonitrile, changed linearly to 5%water: 95% acetonitrile over 5.5 minutes and then maintained at thismixture for 2 minutes.

Method 2

Method 2 employed Waters 515 pumps, a Waters 2525 mixer and a Waters2996 diode array detector. The detection was performed between 210 nmand 650 nm. The mass spectrometer was a Waters micromass ZQ and thecolumn used was a Waters SunFire, 5 μm pore size, C18 of dimensions50×4.60 mm. The injection volume was 10 μl. The mobile phase consistedof a mixture of water and acetonitrile containing 0.1% formic acid. Theeluent flow rate was 1.5 mL/min, using 95% water: 5% acetonitrile,changed linearly to 5% water: 95% acetonitrile over 5.5 minutes and thenmaintained at this mixture for 2 minutes.

Method 3

Method 3 employed Waters 515 pumps, a Waters 2525 mixer and a Waters2487 UV detector (single wavelength 254 nm). The mass spectrometer was aWaters micromass ZQ and the column used was a Waters SunFire, 5 m poresize, C18 of dimensions 50×4.60 mm. The injection volume was 10 μl. Themobile phase consisted of a mixture of water and acetonitrile containing0.1% formic acid. The eluent flow rate was 1.5 mL/min, using 95% water:5% acetonitrile, changed linearly to 5% water: 95% acetonitrile over 5.5minutes and then maintained at this mixture for 2 minutes.

Method 4

Method 4 employed Waters 515 pumps, a Waters 2545 mixer with valvesdirecting to the different columns and a Waters 2996 diode arraydetector. The detection was performed between 210 nm and 650 nm. Themass spectrometer used was a Waters 3100 which detected masses between100 and 700 g/mol. The column used was a XBridge, 5 micron pore size,C18, 50×4.60 mm. The injection volume was 10 μl of a solution (around 1mg/ml). The flow rate was 1.5 mL/min and the mobile phases of water pH10 0.03% ammonium hydroxide) (3 ml/101) and acetonitrile 0.03% ammoniumhydroxide (3 ml/101). The elution was started at 95% water: 5%acetonitrile ramping up to 5% water:95% acetonitrile over 5.50 minutes.The eluent level was returned to the starting conditions of 95% water:5% acetonitrile over 6 seconds. These conditions were held for 1.4minutes to allow equilibration of the column before the next sample wasinjected. The run lasted 7 minutes in total.

Method 5

Method 5 employed Waters 515 pumps, a Waters 2525 mixer with valvesdirecting to the different columns and a Waters 2487 UV detector. Thedetection was done between at 254 nm. The mass spectrometer used was aWaters micromass ZQ which detected masses between 100 and 700 g/mol. Thecolumn used was a SunFire, 5 micron pore size, C18 column of dimensions50×4.60 mm was used. The injection volume was 10 μL of a solution(around 1 mg/mL). The flow rate was 1.5 mL/min and the mobile phases ofwater and methanol contained 0.1% formic acid. The elution was startedat 85% water:15% methanol ramping up to 15% water:85% methanol over 4.5minutes, these conditions were held for 1 minute before the eluent levelwas returned to the starting conditions of 85% water:15% methanol over 6seconds. These conditions were held for 1.4 minutes to allowequilibration of the column before the next sample was injected. The runlasted 7 minutes in total.

Method 6

Method 6 employed Waters 515 pumps, a Waters 2545 mixer with valvesdirecting to the different columns and a Waters 2996 diode arraydetector. The detection was done between 210 nm and 650 nm. The massspectrometer used was a Waters 3100 which detected masses between 100and 700 g/mol. The column used was a XBridge, 5 micron pore size,C18,50×4.60 mm. The injection volume was 10 μL of a solution (around 1mg/mL). The flow rate was 1.5 mL/min and the mobile phases of water pH10 0.03% ammonium hydroxide) (3 ml/101) and methanol0.03% ammoniumhydroxide (3 ml/101). The elution was started at 85% water: 15% methanolramping up to 15% water:85% methanol over 4.5 minutes. These conditionswere held for 1 minute before the eluent level was returned to thestarting conditions of 85% water:15% methanol over 6 seconds.

These conditions were held for 1.4 minutes to allow equilibration of thecolumn before the next sample was injected. The run lasted 7 minutes intotal.

Method 7 Method 7 employed Waters 515 pumps, a Waters 2545 mixer withvalves directing to the different columns and a Waters 2487 UV detector.The detection was done between at 254 nm. The mass spectrometer used wasa Waters micromass ZQ which detected masses between 100 and 700 g/mol.The column used was a SunFire, 5 micron pore size, C18 column ofdimensions 50×4.60 mm was used. The injection volume was 10 μL of asolution (around 1 mg/mL). The flow rate was 1.5 mL/min and the mobilephases of water and methanol contained 0.1% formic acid. The elution wasstarted at 85% water:15% methanol ramping up to 15% water:85% methanolover 4.5 minutes., these conditions were held for 1 minute before theeluent level was returned to the starting conditions of 85% water:15%methanol over 6 seconds. These conditions were held for 1.4 minutes toallow equilibration of the column before the next sample was injected.The run lasted 7 minutes in total.

Method 8

Method 8 employed Waters 515 pumps, a Waters 2525 mixer with valvesdirecting to the different columns and a Waters 2487 UV detector. Thedetection was done between at 254 nm. The mass spectrometer used was aWaters micromass ZQ which detected masses between 100 and 700 g/mol. Thecolumn used was a SunFire, 5 micron pore size, C18 column of dimensions50×4.60 mm was used. The injection volume was 10 μL of a solution(around 1 mg/mL). The flow rate was 1.5 mL/min and the mobile phases ofwater and methanol contained 0.1% formic acid. The elution was startedat 85% water:15% methanol ramping up to 15% water:85% methanol over 3minutes., these conditions were held for 2.5 minute before the eluentlevel was returned to the starting conditions of 85% water:15% methanolover 6 seconds. These conditions were held for 1.4 minutes to allowequilibration of the column before the next sample was injected. The runlasted 7 minutes in total.

Method 9

Method 9 employed Waters 515 pumps, a Waters 2545 mixer with valvesdirecting to the different columns and a Waters 2487 UV detector. Thedetection was done between at 254 nm. The mass spectrometer used was aWaters micromass ZQ which detected masses between 100 and 700 g/mol. Thecolumn used was a XBridge, 5 micron pore size, C18, 50×4.60 mm. Theinjection volume was 10 μL of a solution (around 1 mg/mL). The flow ratewas 1.5 mL/min and the mobile phases of water pH 10 0.03% ammoniumhydroxide) (3 ml/101) and methanol0.03% ammonium hydroxide (3 ml/101).The elution was started at 85% water:15% methanol ramping up to 15%water:85% methanol over 4.5 minutes. These conditions were held for 1minute before the eluent level was returned to the starting conditionsof 85% water: 15% methanol over 6 seconds. These conditions were heldfor 1.4 minutes to allow equilibration of the column before the nextsample was injected. The run lasted 7 minutes in total.

Method 10

LCMS results were obtained on either of two instruments. LCMS analysiswas performed on a Waters Aquity Ultra Performance LC with a 2.1 mm×50mm Waters Aquity UPLC BEH C18 1.7 μm column. The target columntemperature was 45° C., with a run time of two (2) minutes, a flow rateof 0.600 mL/min, and a solvent mixture of 5% (0.1% formicacid/water):95% (acetonitrile/0.1% formic acid). The mass spectrometrydata was acquired on a Micromass LC-ZQ 2000 quadrupole massspectrometer. Alternatively, LCMS analysis was performed on a BrukerEsquire 200 ion trap.

Preparative HPLC Methods

Samples purified by Mass Spectrometry directed High Performance LiquidChromatography employed the following conditions.

Method A

Method A employed Waters 515 pumps, a Waters 2525 mixer and a Waters2487 UV detector (single wavelength 254 nm). The mass spectrometer was aWaters micromass ZQ and the column used was a Waters SunFire, 5 m poresize, C18 of dimensions 50×19 mm. The injection volume was up to 500 Lof solution at a maximum concentration of 50 mg/mL. The mobile phaseconsisted of a mixture of water and acetonitrile containing 0.1% formicacid. The eluent flow rate was 25 mL/min using 95% water, 5%acetonitrile, changing linearly over 5.3 minutes to 95% acetonitrile, 5%water, and maintaining for 0.5 minutes.

Method B

Method B employed Waters 515 pumps a Waters 2545 mixer with valvesdirecting to the different columns and a Waters 2996 diode arraydetector. The detection was performed between 210 nm and 650 nm. Themass spectrometer used was a Waters 3100 which detected masses between100 and 700 g/mol. The column used was a XBridge, 5 micron pore size,C18, 50×19 mm. The injection volume was chosen by the user and can be upto 500 L of the solution (max 50 mg/mL). The flow rate was 25 mL/min andthe mobile phases of water pH 10 0.03% ammonium hydroxide (3 ml/101) andacetonitrile 0.03% ammonium hydroxide (3 ml/101). The elution wasstarted at 95% water:5% acetonitrile ramping up to 5% water:95%acetonitrile over 5.30 minutes. The eluent level was returned to thestarting conditions of 95% water: 5% acetonitrile over 0.6 minutes.These conditions were held for 1.4 minutes to allow equilibration of thecolumn before the next sample was injected. The run lasted 7 minutes intotal.

Analytical HPLC Methods

Method X Method X employs gradient elution (0 to 100%) acetonitrile(containing 0.1% trifluoroacetic acid):water (containing 0.1%trifluoroacetic acid) over five minutes on a 4.6×75 mm (2.5 micron)Zorbax XDB-C8 column at 2.5 ml/min on an Agilent 1100 series HPLC.

Synthesis

Several methods for the chemical synthesis of4-substituted-2-(pyridin-4-yl)-azaquinazoline compounds (forconvenience, collectively referred to herein as “4PAZ compounds”) of thepresent application are described herein. These and/or other well knownmethods may be modified and/or adapted in known ways in order tofacilitate the synthesis of additional compounds within the scope of thepresent application.

In one approach, 4PAZ compounds of general formula [F-001](where A=NH orN alkyl) are prepared by reacting a compound of formula [F-002](where Xis a halogen such as chlorine or a sulfonate) with a compound of formula[F-003](where A is NH or NH2 and Z on the terminal nitrogen is H, alkylor a suitable nitrogen protecting group, such as Boc, Alloc, Cbz orFmoc) in a suitable solvent such as DMF in the presence of a suitablebase such as triethylamine. The reaction is suitably conducted at anelevated temperature for example 40° C. Where Z is a suitable nitrogenprotecting group, such as Boc, Alloc, Cbz or Fmoc, compounds of formula[F-001] are prepared by a suitable deprotection reaction. For example:where Z is a Boc protecting group reaction with an acid such as TFA in asuitable solvent such as DCM. The reaction is suitably conducted atambient temperature. In one approach, compounds of formula [F-001](whereA=O) are prepared by reacting a compound of formula [F-002](where X is ahalogen such as chlorine or sulfonate) with a compound of formula[F-003](where A is OH and Z on the terminal nitrogen is H, alkyl or asuitable nitrogen protecting group, such as Boc, Alloc, Cbz or Fmoc) ina suitable solvent such as DMA in the presence of a suitable base suchas sodium hydride. The reaction is suitably conducted at ambienttemperature. Where Z is a suitable nitrogen protecting group, such asBoc, Alloc, Cbz or Fmoc, compounds of formula [F-001] are prepared by asuitable deprotection reaction. For example: where Z is a Boc protectinggroup reaction with an acid such as TFA in a suitable solvent such asDCM. The reaction is suitably conducted at ambient temperature.

In one approach, compounds of formula [F-002](where X is a halogen suchas chlorine) are prepared by reacting a compound of formula [F-004] witha suitable halogenating agent such as phosphorous oxychloride. Thereaction is suitably conducted at elevated temperature such as 125° C.Compounds of formula [F-002](where X is a sulfonate) are prepared byreacting a compound of formula [F-004] with a suitably substitutedsulfonyl chloride in a suitable solvent such as DMA in the presence of asuitable base such as triethylamine and a catalytic amount of DMAP. Thereaction is suitably conducted at ambient temperature.

In one approach, compounds of formula [F-004] are prepared by reacting acompound of formula [F-005](where Rx is an alkyl group such as methyl orethyl) with a compound of formula [F-006] in a suitable solvent in a drynon-aprotic solvent such as dioxane or THF in the presence of a hinderedalkoxide base such as potassium-tert-pentylate 1.7M in toluene orpotassium-tert-butoxide. The reaction is suitably conducted at ambienttemperature.

In one approach, compounds of formula [F-004] are prepared by reacting acompound of formula [F-007] with a compound of formula [F-006] in asuitable solvent in a protic solvent such as methanol in the presence ofa base such as sodium methoxide. The reaction is suitably conductedfirst at ambient temperature then at reflux overnight.

An example of a method as described above is illustrated in thefollowing scheme.

General Synthesis of4-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine Derivatives ofGeneral Formula [F-001] Scheme A1

Substituted 2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives ofgeneral formula [F-001] were prepared by the reaction of a2-amino-pyridyl derivative of general formula [F-005] with a4-cyanopyridyl derivative of general formula [F-006] in the presence ofa base such as sodium methoxide in a polar aprotic solvent such asmethanol. The reaction is suitably conducted at elevated temperature toyield the cyclised 2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol product ofgeneral formula [F-004].4-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F-001] were prepared by the reaction of a2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives of generalformula [F-004] with a chlorinatation agent such as phosphorousoxychloride to yield4-chloro-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F-008] which were reacted with primary or secondaryamino derivative of general formula [F-003], in a polar aprotic solventsuch as DMA, DMF, NMP in the presence of a tertiary amine base such asEt3N, DIPEA or NMM at ambient temperature [method A]. After reactionwork up, typically by a liquid-liquid extraction or purification byacidic ion exchange catch-release, the N-Boc derivatives weredeprotected under acidic conditions with a strong acid such as TFA, TCA,methanesulfonic acid, HCl or H₂SO₄ in a solvent such as DCM, DCE, THF,EtOH or MeOH and the crude reaction product was purified by normal phasesilica gel chromatography or reverse phase preparative HPLC.4-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F-001] were prepared by the reaction of a2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives of generalformula [F-004] with 2,4,6-triisopropylbenzenesulfonyl chloride in apolar aprotic solvent such as DMA, DMF, NMP with a tertiary alkylaminebase such as Et₃N, DIPEA or NMM and a catalytic amount of DMAP [methodB]. The intermediate 6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester was then reactedwith a primary or secondary amino derivative, of general formula[F-003], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, theN-Boc derivatives were deprotected under acidic conditions with a strongacid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in a solventsuch as DCM, DCE, THF, EtOH or MeOH and the crude reaction product waspurified by reverse phase preparative HPLC

Synthesis of 4-Piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine[1]Method A

Synthesis of 2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol [A001]

A mixture of 4-Cyanopyridine (8.25 g, 79.2 mmol), sodium methoxide (891mg, 16.5 mmol) and methanol (400 mL) was stirred at room temperature for60 minutes. 3-Amino-isonicotinic acid (9.12 g, 66.0 mmol) was added andthe mixture heated to reflux for 3 days. After cooling to roomtemperature the solid precipitate was collected by filtration then driedin the vacuum oven to yield the title compound as an off-white solid(6.02 g): (1H, 300 MHz, d6-dmso) 13.10 (1H, br s), 9.16 (1H, s), 8.80(2H, dd), 8.70 (1H, d), 8.10 (2H, dd), 8.00 (1H, dd)

Synthesis of 4-Chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine [A002]

2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol [A001](4 g, 17.8 mmol) inPOCl₃ (50 mL, 538 mmol) was heated to 110° C. for 3 hours. The reactionmixture was concentrated under vacuum, quenched with saturated NaHCO₃solution, extracted into DCM, washed with water then brine, passedthrough a phase separator cartridge and evaporated to yield the titlecompound [A002] (2.6 g) as a yellow/brown solid which was used withoutfurther purification: LCMS method: 1, RT:4.09 min, MI 243 [M+H].

Synthesis of1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine[1]

A solution of 4-Chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine [A002](100mg, 0.43 mmol), piperazine (172 mg, 2 mmol) in anhydrous DMA (5 mL) wasstirred at room temperature for 3 days. The reaction mixture waspartitioned between NaOH (2M aqueous solution) and ethyl acetate. Theorganic layer was further washed with water then brine, dried (MgSO₄),passed through a phase separator cartridge and evaporated to yield thecrude material, which was purified by preparative HPLC (method A) toyield the title compound (1.87 mg). LCMS method: 1, RT:3.49 min, MI 293[M+H]; 1H-NMR (300 MHz; DMSO-d6): 9.26 (1H, s), 8.76 (2H, d), 8.58 (1H,d), 8.32 (2H, d), 8.24 (1H, s), 7.92 (1H, d), 3.96 (4H, br tr), 2.99(4H, br tr)

Synthesis of(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine[2]methodB

Synthesis of 5-Methoxy-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[A003]

To a stirred solution of 2-chloro-4-pyridinecarbonitrile (1 g, 9.6 mmol)in MeOH (20 mL) was added 0.5 M NaOMe (2 mmol, 4 mL) followed by3-Amino-5-methoxy-isonicotinic acid (1.35 g, 8 mmol). The RM was heatedat 75° C. over night. The RM was left to cool and a solid ppt formedwhich was collected by filtration, washed with cold MeOH and dried in avac oven to give the title compound as a pale brown solid (610 mg, 30%yield). LCMS method: 1, RT:3.82 min, MI 255.09 [M+H].

Synthesis of(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine[2]

5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-[A003](0.157 mmol,0.04 g), 2,4,6-triisopropylbenzenesulfonyl chloride (0.173 mmol, 0.052g), were dissolved in anhydrous DMA (2 mL), and Et₃N (0.314 mmol, 0.045mL), and DMAP (5 mg) were added sequentially. The mixture was stirred atroom temperature for 1 hour and (R)-3-amino-pyrrolidine-1-carboxylicacid tert-butyl ester (0.236 mmol, 0.044 g) was added. The mixture wasstirred at room temperature overnight. The solvent was then removedunder reduced pressure and the residue was stirred in trifluoroaceticacid (1 mL) at room temperature for 3 h. The solution was poured on toan SCX-2 cartridge (5 g), washed with methanol (10 mL) and then washedwith ammonia (2N in methanol, 2 0 mL). The ammonia washes wereconcentrated in vacuo to a brown residue that was purified bypreparative HPLC (method A) to yield the title compound (0.016 g). LCMSmethod: 1, RT: 1.47 min, MI 323 [M+H]; 1H-NMR 300 MHz (1H d6-dmso) 8.81(1H, s), 8.76 (2H, dd), 8.35 (1H, s), 8.32 (2H, dd), 8.23 (1H, d), 6.42(1H, s), 4.98 (1H, m), 4.14 (3H, s), 3.19-3.07 (2H, m), 2.41-2.29 (2H,m), 2.07-1.95 (2H, m).

Synthesis of 2-(3-Fluoro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol[A004]

2-(3-Fluoro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol [A004]

3-Amino-2-chloro-isonicotinamide (0.5 g, 3.64 mmol),3-Fluoroisonicotinaldehyde (0.54 g, 4.37 mmol), NaHSO3 (0.75 g, 7.29mmol) and DMA (5 mL) were added successively to a microwave vial. Thevial was sealed then heated at 160° C. for 6 min. Water (10 mL) wasadded and the resulting solid was filtered and used without furtherpurification. LCMS method: 1, RT:3.07 min, MI 243 [M+H]

Synthesis of 8-Chloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[A005]

8-Chloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [A005]

A solution of 3-Amino-2-chloro-isonicotinamide (0.5 g, 2.91 mmol) and4-Pyridinecarboxaldehyde (0.35 g, 3.32 mmol) in DMA (10 mL) was heatedunder microwave (100° C., 2h). Sodium hydrogen sulfite (0.606 g, 5.83mmol) was then added and the mixture was heated under microwave (150°C., 1 h). Water was then added to the mixture and the resulting solid(0.34 g, 45%) was collected, washed with water and then by MeOH. LCMSmethod: 1, RT:3.89 min, MI 258 [M+H]

Synthesis of 8-Chloro-2-Pyridin-4-Yl-3H-Pyrido[3,4-d]Pyrimidin-4-One[A005]

Synthesis of 2-Chloro-3-[(pyridine-4-carbonyl)-amino]-isonicotinamide[A006]

To a suspension of 3-Amino-2-chloro-isonicotinamide (0.5 g, 2.913 mmol)and K₂CO₃ (1 g, 7.28 mmol) in refluxing Et₂O (25 mL), Isonicotinoylchloride hydrochloride (0.622 g, 3.5 mmol) was added portionwise. Themixture was stirred under reflux for 4h. The solvent was removed underreduced pressure and water (50 mL) was added. The resulting solid wasfiltered, washed with H₂O and then collected, dried with an azeotropewith toluene, to yield the title compound (0.78 g, 96%) which was usedwithout further purification. LCMS method: 1, RT:2.55 min, MI 277 [M+H]

Synthesis of 8-Chloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[A004]

To a solution of2-Chloro-3-[(pyridine-4-carbonyl)-amino]-isonicotinamide [A006](0.2 g,0.723 mmol) in MeOH (20 mL) was added a solution of cesium carbonate(0.47 g, 1.44 mmol) in H₂O (2 mL). The mixture was stirred at roomtemperature overnight. The MeOH was removed under reduced pressure andwater (10 mL) was added. Acetic acid was added slowly and the resultingsolid was collected, dried with a toluene azeotrope to yield the titlecompound which was used without further purification. LCMS method: 1,RT:3.43 min, MI 259 [M+H]

Synthesis of 6-Chloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[A007]

6-Chloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [A007]

A solution of potassium pentoxide (2.6 mL, 5.1 mmol, 25% soln inToluene) was added dropwise (˜0.5 mL/min) to a solution of5-Amino-2-chloro-isonicotinic acid ethyl ester (0.4 g, 2 mmol) and4-cyanopyridine (0.25 g, 2.4 mmol) in anhydrous THF (5 mL) cooled in anice bath. The reaction was allowed to warm to RT and left to stir atroom temperature overnight. Water (9 mL) was added and the mixture wasstirred at RT for 20 mins. Acetic acid (˜1 mL) was then added and themixture was left to stir at RT and the resulting yellow precipitate wasfiltered and the siolid washed with deionised water (2×3 mL). To givethe title compound (0.43 g, 83% yield). LCMS method: 1, RT: 2.21 min, MI259 [M+H]

Synthesis of2-(3-Fluoro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol [A008]

2-(3-Fluoro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol [A008]To a stirred solution of 3-Fluoroisonicotinonitrile (0.088 g, 0.71 mmol)in MeOH (5 mL) was added NaOMe (0.008 g, 0.15 mmol). After 1 hr3-amino-5-methoxy-isonicotinic acid (0.1 g, 0.54 mmol) was added and theRM heated to 85° C. for 18 hr. The solution became yellow in colour. Thereaction mixture was alloed to cool to RT and the white solid wascollected by filtration and washed with MeOH to yield the title compound(0.07 g, 43% yield). LCMS method: 1, RT:1.19 min, MI 271.24 [M+H]

The following compounds were synthesised according to the generalsynthesis shown in scheme [A1]:

Pre- Meth- Amine Analysis Ex cursor od [F-003] LCMS NMR Name 3 [A001] A

Method 1: RT: 2.2 min, MI: 267 [M + H] N-(2-aminoethyl)-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4-amine 4 [A001 A

Method 1: RT: 2.45 min, MI, 281 [M + H] N-[(2R)-2- aminopropyl]-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-amine 5 [A001] A

Method 1: RT: 2.52 min, MI, 281 [M + H] N-[(2S)-2- aminopropyl]-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-amine 6 [A001] B

Method 1: RT: 2.51 min, MI, 357 [M + H] (1H, 300 MHz, d6-dmso); 9.15 ppm(1H, d), 8.70 ppm (2H, d), 8.62 ppm (2H, d), 8.20 ppm (1H, d), 8.12 ppm(2H, d), 7.35-7.26 ppm (5H, m), 3.86 ppm, (1H, d), 3.35 ppm (2H, m),2.27 ppm (2H, m) N-[(2S)-2-amino-3- phenylpropyl]-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4-amine 7 [A001] B

Method 1: RT: 0.88 min, MI, 293 [M + H] (1H, 300 MHz, d6-dmso), 9.18(1H, s), 8.94-8.90 (1H, m), 8.76 (2H, dd), 8.65 (1H, d), 8.35 (2H, dd),4.94-4.85 (1H, m), 3.87-3.74 (3H, m), 3.19-3.07 (2H, m), 2.30-2.18 (2H,m), 2.02-1.92 (2H, m) (3R)-N-[2-(pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]pyrrolidin-3-amine 8 [A004] B

Method 1: RT: 0.5 min, MI, 311 [M + H] (1H, 300 MHz, d6-dmso), 9.47 (1H,brd), 9.15 (1H, s), 8.71 (1H, d), 8.66 (1H, d), 8.57 (1H, d), 8.47 (1H,s), 8.39 (1H, d), 8.08 (1H, dd), 4.92 (1H, br s), 3.46 (1H, dd),3.34-3.22 (2H, m), 2.30-2.20 (1H, m), 2.18-2.08 (1H, m) (3R)-N-[2-(3-fluoropyridin-4- yl)pyrido[3,4- d]pyrimidin-4- yl]pyrrolidin-3-amine 9[A003] B

Method 1: RT: 2.92 min, MI, 387 [M + H] (1H, 300 MHz, d6-dmso); 8.72(1H, s), 8.68 (2H, d), 8.28 (1H, s), 8.00 (2H, d), 7.39-7.30 (5H, m),4.00 (3H, s), 3.96-3.91 (1H, m), 3.59 (2H, br s), 3.00 (1H, dd), 2.79(1H, dd) N-[(2S)-2-amino-3- phenylpropyl]-5- methoxy-2-(pyridin-4-yl)pyrido[3,4- d]pyrimidin-4-amine 10 [A004] B

Method 1: RT: ,2.95 min MI, 375 [M + H] (1H, 300 MHz, d6-dmso), 9.12(1H, s), 8.69 (1H, d), 8.53 (1H, d), 8.46 (1H, S), 8.21 (1H, d), 7.83(1H, dd), 7.28-7.19 (5H, m), 3.81 (1H, dd), 3.66-3.49 (2H, m), 2.90 (1H,dd), 2.80 (1H, dd), N-[(2S)-2-amino-3- phenylpropyl]-2-(3-fluoropyridin-4- yl)pyrido[3,4- d]pyrimidin-4-amine 11 [A005] B

Method 1: RT: 2.98 min, MI: 392 [M + H] (1H, 300 MHz, d6-dmso), 8.70(2H, d), 8.40 (1H, d), 8.36 (1H, br s), 7.98 (2H, d), 7.43-7.32 (5H, m),3.97 (1H, d), 3.69-3.54 (2H, m), 3.06 (1H, dd), 2.84 (1H, dd)N-[(2S)-2-amino-3- phenylpropyl]-8- chloro-2-(pyridin-4- yl)pyrido[3,4-d]pyrimidin-4-amine 12 [A007] A

Method 1: RT: 6.51 min, MI: 391 [M + H] (1H, 300 MHz, d6-dmso) 9.06 s),8.69 (2H, dd), 7.98 (2H, dd), 7.87 (1H, s), 7.42-7.27 (5H, m), 4.54 (1H,dd), 4.37 (1H, d), 3.58- 3.48 (1H, m), 3.04-2.93 (3H, m), 2.85-2.59 (3H,m) N-[(2S)-2-amino-3- phenylpropyl]-6- chloro-2-(pyridin-4-yl)pyrido[3,4- d]pyrimidin-4-amine 13 [A007] A

Method 1: RT: 4.35 min, MI: 327 [M + H] (300 MHz, 1H, d6-dmso) 9.20 (1H,s), 8.79 (2H, d), 8.35 (2H, d), 8.13 (1H, s), 6.61 (1H, s), 4.15 (4H, brs), 3.33 (4H, br s) 1-[6-chloro-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperazine 14 [A007] A

Method 1: RT: 2.91 min, MI: 443.9 [M + H] (300 MHz, 1H, d6-dmso) 9.06(1H, s), 8.69 (2H, dd), 7.98 (2H, dd), 7.87 (1H, s), 7.41-7.29 (5H, m),4.54 (1H, dd), 4.37 (1H, d), 3.53 (1H, dt), 3.03-2.93 (3H, m), 2.85-2.57 (3H, m) (3S)-3-benzyl-1-[6- chloro-2-(pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperazine 15 [A001] A

Method 1: RT: 4.30 min, MI: 358 [M + H] (300 MHz, 1H, d4-MeOH) 8.55 (d,1H), 8.22 (dd, 2H), 8.03 (dd, 1H), 7.76 (m, 5H), 4.28 (m, 1H), 4.09 (1H,dd), 3.58 (1H, dd), 2.96 (1H, dd), 2.88 (1H, dd) (2S)-1-phenyl-3-{[2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- yl]amino}propan-2- ol 16[A001] A

Method 1: RT: 2.44 min, MI: 383 [M + H] (1H, 300 MHz, CDCl₃): 9.34 (s,1H), 8.73 (d, 2H), 8.46 (d, 1H), 8.21 (d, 2H), 7.49 (d, 1H), 7.33 (m,3H), 7.25 (d, 2H), 4.58 (d, 1H), 4.48 (d, 1H), 3.46 (t, 1H), 3.02 (m,4H), 2.76 (m, 2H) (3S)-3-benzyl-1-[2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperazine 17 [A001] A

Method 1: RT: 2.45 min, MI: 383 [M + H] (1H, 300 MHz, CDCl₃): 9.34 (s,1H), 8.73 (d, 2H), 8.46 (d, 1H), 8.21 (d, 2H), 7.49 (d, 1H), 7.33 (m,3H), 7.25 (d, 2H), 4.58 (d, 1H), 4.48 (d, 1H), 3.46 (t, 1H), 3.02 (m,4H), 2.76 (m, 2H) (3R)-3-benzyl-1-[2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperazine 18 [A001] A

Method 1: RT: 3.99 min, MI: 307 [M + H] (1H, 300 MHz, d6-dmso) 9.26 (1H,s), 8.75 (2H, dd), 8.58 (1H, d), 8.31 (2H, dd), 7.91 (1H, d), 3.98-3.96(4H, m), 2.55-2.52 (4H, m), 2.25 (3H, s) 1-methyl-4-[2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine 19 [A001] A

Method 1: RT: 4.00 min, MI: 321 [M + H] (1H, 300 MHz, d6-dmso) 9.19 (1H,s), 8.75 (2H, dd), 8.52 (1H, d), 8.29 (2H, dd), 7.98 (1H, d), 4.13-4.06(4H, m), 2.85-2.83 (2H, m), 2.55-2.51 (2H, m), 2.26 (3H, s), 2.10-2.03(2H, m) 1-methyl-4-[2- (pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]-1,4-diazepane 20 [A001] A

Method 1: RT: 4.29 min, MI: 473 [M + H] (1H, 300 MHz, CDCl₃): 9.31 (s,1H), 8.75 (d, 2H), 8.47 (d, 1H), 8.30 (d, 2H), 7.49 (d, 1H), 7.36 (m,5H), 7.02 (m, 5H), 5.02 (s, 1H), 4.30 (d, 1H), 3.90 (td, 1H), 3.62 (d,1H), 3.45 (d, 1H), 3.26 (m, 2H), 3.04 (d, 1H), 2.92 (d, 1H), 2.35 (m,2H) (2S)-2,4-dibenzyl-1- [2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]piperazine 21 [A001] A

Method 1: RT: 2.86 min, MI: 294 [M + H] (1H, 300 MHz, d6-dmso) 9.28 (1H,s), 8.76 (2H, d), 8.59 (1H, d), 8.33 (2H, d), 7.97 (1H, d), 4.02-3.99(4H, t), 3.83-3.80 (4H, t) 4-[2-(pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]morpholine 22 [A001] A

Method 1: RT: 4.76 min, MI: 349 [M + H] (1H, 300 MHz, d6-dmso) 9.28 (1H,s), 8.77 (2H, dd), 8.60 (1H, d), 8.34 (2H, dd), 7.97 (1H, d), 4.03-4.00(4H, m), 3.61 (4H, br s), 1.43 (9H, s) tert-butyl 4-[2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine-1- carboxylate 23 [A001] A

Method 1: RT: 4.18 min, MI: 407 [M + H] (1H, 300 MHz, d6-dmso) 9.22 (1H,s), 8.76 (2H, dd), 8.56 (1H, d), 8.30 (2H, dd), 8.08-8.03 (1H, m), 4.28-4.22 (2H, m), 4.15-4.10 (2H, m), 3.72-3.65 (2H, m), 3.42 (2H, br s),2.09-1.97 (2H, m), 1.11 (4H, s), 0.93 (5H, s) tert-butyl 4-[2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]- 1,4-diazepane-1-carboxylate 24 [A001] A

Method 1: RT: 3.8 min, MI: 310 [M + H] (1H, 300 MHz, d6-dmso) 9.29 (1H,s), 8.76 (2H, dd), 8.60 (1H, d), 8.32 (2H, dd), 7.87 (1H, d), 4.23-4.20(4H, m), 2.93-2.89 (4H, m) 4-[2-(pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]thiomorpholine 25 [A001] A

Method 1: RT: 2.34 min, MI: 385 [M + H] (1H, 300 MHz, d6-dmso) 9.13 (1H,s), 8.67 (2H, dd), 8.61 (1H, d), 8.15 (1H, d), 7.99 (2H, d), 7.37-7.26(5H, m), 3.76 (2H, br s), 3.33-3.13 (1H, m), 3.07-2.88 (2H, m), 2.35(6H, br s) N,N-Dimethyl[(2S)- 1-phenyl-3-{[2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]amino}propan-2- yl]amine 26 [A001] A

Method 1: RT: 2.44 min, MI: 371 [M + H] (1H, 300 MHz, d6-dmso) 9.15 (1H,s), 8.77-8.75 (2H, m), 8.64 (1H, d), 8.30-8.28 (2H, m), 8.24 (1H, d),7.32-7.29 (2H, m), 7.20-7.15 (2H, m), 7.09-7.04 (1H, m), 5.08- 4.99 (1H,m), 3.11-2.87 (4H, m), 2.38 (3H, s). N-[(2S)-2-amino-3- phenylpropyl]-N-methyl-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-amine 27 [A001] A

Method 1: RT: 2.21 min, MI: 307 [M + H] 1H NMR (d6-DMSO, 300 MHz) 9.28(1H, s), 8.77 (2H, d), 8.61 (1H, d), 8.34 (2H, d), 8.31 (1H, s), 8.03(1H, d), 4.51 (2H, s), 4.18 (2H, t), 3.53-3.43 (2H, m). 4-[2-(pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]piperazin-2-one 28 [A001] A

Method 1: RT: 2.44 min, MI: 357 [M + H] — N-[(2S)-1-amino-3-phenylpropan-2-yl]- 2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-amine 29[A001] A

Method 1: RT: 2.12 min, MI: 383.18 [M + H] (1H, 300 MHz, CDCl₃): 9.27(s, 1H), 8.75 (d, 2H), 8.47 (d, 1H), 8.29 (d, 2H), 7.45 (d, 1H), 7.11(m, 5H), 5.05 (m, 1H), 4.28 (d, 1H), 3.83 (dt, 1H), 3.23 (m, 3H), 3.09(m, 2H), 3.01 (dt, 1H). (2R)-2-benzyl-1-[2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperazine 30 [A003] B

Method 1: RT: 2.71 min, MI: 413.17 [M + H] (1H, 500 MHz, d6-dmso) 8.77(s, 1H), 8.69 (d, 2H), 8.22 (s, 1H), 8.03 (d, 2H), 7.34 (m, 3H), 7.27(d, 2H), 4.27 (m, 1H), 4.02 (m, 1H), 3.90 (s, 3H), 3.22 (t, 1H), 2.99(m, 2H), 2.83 (t, 1H), 2.72 (dd, 1H), 2.63 (t, 1H), 2.62 (dd, 1H).(3S)-3-benzyl-1-[5- methoxy-2-(pyridin- 4-yl)pyrido[3,4- d]pyrimidin-4-yl]piperazine 31 [A003] B

Method 1: RT: 1.261 min, MI: 323.07 [M + H] (1H, 300 MHz, d6-dmso) 8.86(1H, t), 8.78-8.76 (2H, m), 8.36 (1H, s), 8.32-8.30 (2H, m), 4.08 (3H,s), 3.75 (4H, m), 3.03 (4H, m). 1-[5-methoxy-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine 32 [A005] B

Method 1: RT: 1.39 min, MI: 327 [M + H] (1H, 300 MHz, d6-dmso): 8.79 (d,2H), 8.32-8.37 (m, 3H), 7.92 (d, 1H), 3.94 (brs, 4H), 2.95 (brs, 4H).1-[8-chloro-2- (pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine33 [A001] A

Method 1: RT: 3.92 min, MI: 307 [M + H] (1H, 300 MHz, d6-dmso) 9.21 (1H,s), 8.77-8.75 (2H, m), 8.54 (1H, d), 8.32-8.30 (2H, m), 8.00 (1H, d),4.14-4.07 (4H, m), 3.15-3.12 (2H, m), 2.85-2.81 (2H, m), 2.04-1.97 (2H,m). 1-[2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]- 1,4-diazepane 34[A001] A

Method 1: RT: 4.04 min, MI: 337 [M + H] (1H, 300 MHz, d6-dmso) 9.27 (1H,s), 8.78-8.76 (2H, m), 8.60 (1H, d), 8.34-8.32 (2H, m), 7.94 (1H, d),4.50 (1H, br m), 4.00 (4H, br m), 3.60-3.54 (2H, m), 2.67 (4H, br m),2.49-2.46 (2H, m). 2-{4-[2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]piperazin-1- yl}ethan-1-ol 35 [A001] A

Method 1: RT: 2.35 min, MI: 294 [M + H] (1H, 300 MHz, d6-dmso) 9.19 (1H,s), 8.77-8.74 (2H, m), 8.56 (1H, d), 8.34-8.32 (2H, m), 8.17 (1H, br m),5.18 (1H, d), 4.49 (1H, br m), 4.08 (3H, br m), 3.88 (1H, br d), 2.05(2H, br m). (3S)-1-[2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]pyrrolidin-3-ol 36 [A001] A

Method 1: RT: 2.39 min, MI: 294 [M + H] (1H, 300 MHz, d6-dmso) 9.19 (1H,s), 8.77-8.74 (2H, m), 8.56 (1H, d), 8.34-8.32 (2H, m), 8.17 (1H, br m),5.18 (1H, d), 4.49 (1H, br m), 4.08 (3H, br m), 3.88 (1H, br d), 2.05(2H, br m). (3R)-1-[2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]pyrrolidin-3-ol 37 [A003] B

Method 1: RT: 2.74 min, MI: 413.17 [M + H] (1H, 500 MHz, d6-dmso): 8.79(s, 1H), 8.70 (d, 2H), 8.23 (s, 1H), 8.05 (d, 2H), 7.33 (m, 3H), 7.27(d, 2H), 3.21 (t, 1H), 3.17 (d, 2H), 3.00 (d, 1H), 2.92 (m, 1H), 2.82(t, 1H), 2.76 (dd, 1H), 2.68 (d, 1H), 2.61 (dd, 1H). (3R)-3-benzyl-1-[5-methoxy-2-(pyridin- 4-yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine 38[A001] A

Method 1: RT: 2.06 min, MI: 383.17 [M + H] (1H, 500 MHz, CDCl₃): 9.29(s, 1H), 8.75 (d, 2H), 8.47 (d, 1H), 8.28 (d, 2H), 7.45 (d, 1H), 7.09(m, 5H), 5.04 (m, 1H), 4.25 (d, 1H), 3.83 (t, 1H), 3.28 (m, 2H), 3.22(d, 1H), 3.09 (m, 2H), 3.02 (t, 1H). (2S)-2-benzyl-1-[2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine 39 [A001] A

Method 1: RT: 1.04 min, MI: 351.25 [M + H] (1H, 300 MHz, d4-MeOH): 9.20(s, 1H), 8.71 (dd, 2H), 8.59 (d, 1H), 8.48 (dd, 2H), 8.08 (d, 1H), 4.98(m, 1H), 4.99 (m, 1H), 4.02 (dd, 1H), 3.74 (s, 3H), 3.42 (dd, 1H), 3.25(dd, 1H), 2.78 (m, 2H), 2.21 (m, 1H). methyl (2S,4S)-4- {[2-(pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]amino}pyrrolidine- 2-carboxylate 40[A001] A

Method 1: RT: 0.52 min, MI: 463 [M + H] (1H, 300 MHz, d4-MeOH): 9.21 (s,1H), 8.71 (ss, 2H), 8.60 (d, 1H), 8.50 (dd, 2H), 8.09 (d, 1H), 4.99 (m,1H), 4.29 (m, 1H), 3.86 (m, 2H), 3.73 (s, 3H), 3.47 (dd, 1H), 3.14 (m,2H), 2.89 (dd, 1H), 2.74 (m, 1H), 2.49 (m, 1H), 2.12 (m, 1H), 1.88 (m,1H). methyl (2S,4S)-4- [(2S,4S)-4-{[2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]amino}pyrrolidine- 2-amido]pyrrolidine- 2-carboxylate41 [A003] A

Method 1: RT: 5.14 min, MI: 401 [M + H] (1H, 300 MHz, d6-dmso) 8.77 (s,1H), 8.72-8.70 (2H, m), 8.33 (1H, s), 8.20 (1H, s), 8.12- 8.10 (2H, m),7.33-7.23 (5H, m), 4.12 (3H, s), 3.86-3.78 (1H, m), 3.62-3.53 (1H, m),3.18-3.11 (1H, m), 2.98-2.92 (1H, m)2.71- 2.64 (1H, m), 2.45 (3H, s).[(2S)-1-{[5-methoxy- 2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]amino}-3- phenylpropan-2- yl](methyl)amine 42 [A001] A

Method 1: RT: 3.0 min, MI: 294 [M + H] (1H, 300 MHz, d6-dmso) 9.21 (1H,s), 8.81-8.77 (3H, m), 8.67 (1H, d), 8.37-8.33 (3H, m), 6.57 (2H, s),5.00-4.90 (1H, m), 4.14-4.09 (1H, m), 4.01-3.94 (1H, m), 3.86-3.79 (2H,m), 2.42- 2.33 (1H, m), 2.20-2.09 (1H, m). N-[(3R)-oxolan-3-yl]-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-amine 43 [A003] B

Method 1: RT: 3.41 min, MI: 391.13 [M + H] (1H, 300 MHz, CDCl₃): 9.01(s, 1H), 8.76 (d, 2H), 8.31 (d, 2H), 8.22 (s, 1H), 4.42 (d, 1H),4.15-4.04 (m, 1H), 4.07 (s, 3H), 3.62 (br m, 1H), 3.33-3.12 (m, 3H),3.00 (t, 1H). 1-[5-methoxy-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4-yl]-3- (trifluoromethyl)piper- azine 44 [A003] B

3jdf138qc, 96%, 337.23, 1.37 min, + [M + H] LC- MS17QC (1H, 300 MHz,CDCl₃): 8.95 (s, 1H), 8.74 (d, 2H), 8.31 (d, 2H), 8.16 (s, 1H), 4.20 (t,2H), 4.05 (s, 3H), 3.16 (m, 2H), 2.99 (m, 2H), 2.81 (t, 1H), 1.14 (d,3H). (3S)-1-[5-methoxy-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4-yl]-3- methylpiperazine 45 [A003] B

Method RT: 1.52 min, MI: 323 [M + H] (1H, 300 MHz, d6-dmso) 8.80 (1H,s), 8.78-8.75 (2H, m), 8.34 (1H, s), 8.32-8.30 (2H, m), 4.07 (3H, s),3.94 (2H, br s), 3.82 (1H, br s), 3.72 (1H, br s), 2.15 (1H, br s), 1.10(1H, br s). (3R)-1-[5-methoxy- 2-(pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]pyrrolidin-3-amine 46 [A003] B

Method 1: RT: 1.32 min, MI: 353.2 [M + H] (1H, 300 MHz, d6-dmso): 8.84(s, 1H), 8.76 (d, 2H), 8.34 (s, 1H), 8.29 (d, 2H), 4.87 (bs, 1H), 4.28(dd, 2H), 4.06 (s, 3H), 3.43 (m, 1H), 3.07 (m, 3H), 2.82 (m, 3H).[(2R)-4-[5-methoxy- 2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]piperazin-2- yl]methanol 47 [A003] B

Method 1: RT: 2.79 min, MI: 405.22 [M + H] (1H, 300 MHz, CDCl₃): 8.90(s, 1H), 8.72 (d, 2H), 8.22 (d, 2H), 8.14 (s, 1H), 7.40 (m, 5H), 5.43(dd, 1H), 4.18 (m, 1H), 4.10 (s, 3H), 3.53 (m, 2H). N-[(2R,3R)-2-amino-3-fluoro-3- phenylpropyl]-5- methoxy-2-(pyridin- 4-yl)pyrido[3,4-d]pyrimidin-4-amine 48 [A003] B

Method 1: RT: 3.76 min, MI: 470.24 [M + H] (1H, 300 MHz, CDCl₃): 8.94(s, 1H), 8.70 (d, 2H), 8.12 (d, 2H), 8.05 (s, 1H), 7.28 (m, 2H), 7.08(m, 3H), 4.04 (d, 1H), 3.84 (m, 4H), 3.65 (m, 1H), 3.56 (d, 1H), 3.29(m, 1H), 3.06 (m, 3H), 2.89 (m, 1H), 2.66 (dt, 1H), 2.53 (dd, 1H).2-[(2S)-2-benzyl-4- [5-methoxy-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperazin-1- yl]acetamide 49 [A003] A

Method 1: RT: 5.71 min, MI: 415 [M + H] (1H, 300 MHz, d4-MeOH) 8.63 (1H,s), 8.58-8.56 (2H, m), 8.10 (1H, s), 8.06-8.04 (2H, m), 7.31-7.19 (5H,m), 4.06 (3H, m), 3.98-3.91 (1H, m), 3.71-3.63 (1H, m), 3.59-3.47 (1H,m), 3.20- 3.14 (1H, m), 2.67-2.60 (7H, m). [(2S)-1-{[5-methoxy-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- yl]amino}-3- phenylpropan-2-yl]dimethylamine 50 [A003] B

Method 1: RT: 3.69 min, MI: 324.19 [M + H] (1H, 300 MHz, CDCl₃) 8.92(1H, s), 8.74-8.72 (2H, m), 8.36-8.34 (2H, m), 8.16 (1H, m), 4.62 (1H,br s), 4.26-4.16 (1H, m), 4.07 (3H, m), 3.82-3.75 (1H, m), 3.63 (1H, d),2.12-2.20 (1H, m), 1.22-1.21 (2H, m). (3S)-1-[5-methoxy-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]pyrrolidin-3-ol 51 [A003] B

Method 1: RT: 0.63 min, MI: 351 [M + H] (1H, 300 MHz, CDCl₃): 8.97 (s,1H), 8.78 (d, 2H), 8.31 (d, 2H), 8.19 (s, 1H), 4.23 (m, 2H), 4.07 (s,3H), 3.08 (m, 2H), 2.75 (t, 2H), 1.16 (m, 6H). 1-[5-methoxy-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]- 3,5-cis-dimethylpiperazine 52 [A003] B

Method 1: RT: 4.03 min, MI: 337.37 [M + H] (1H, 300 MHz, CDCl₃): 8.98(s, 1H), 8.77 (d, 2H), 8.32 (d, 2H), 8.19 (s, 1H), 4.22 (t, 2H), 4.07(s, 3H), 3.19 (m, 2H), 3.05 (m, 2H), 2.82 (m, 1H), 1.15 (d, 3H).(3R)-1-[5-methoxy- 2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]-3-methylpiperazine 53 [A003] B

1H NMR (300 MHz, d₆-DMSO) 8.78-8.73 (3H, m), 8.30-8.28 (3H, m), 4.05(3H, s), 3.92 (4H, m), 3.36 (3H, m) (3S)-1-[5-methoxy-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]pyrrolidin-3-amine 54 [A003] B

Method 1: RT: 1.48 min, MI: 355.15 [M + H] (1H, 300 MHz, CDCl₃) 9.02(1H, s), 8.80-8.78 (2H, m), 8.35-8.33 (2H, m), 8.22 (1H, m), 4.59-4.57(1H, m), 4.44-4.41 (1H, m), 4.28 (1H, d), 4.22-4.16 (1H, m), 4.10 (3H,s), 3.25-3.20 (1H, m), 3.12- 3.03 (1H, m). 3-(fluoromethyl)-1-[5-methoxy-2- (pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine 55[A001] A

Method 1: RT: 4.22 min, MI: 377.43 [M + H] (1H, 300 MHz, d6-dmso) 9.25(1H, s), 8.75 (2H, dd), 8.58 (1H, d), 8.31 (2H, dd), 7.89 (1H, d), 7.74(1H, d), 4.58 (2H, d), 3.86- 3.79 (1H, m), 3.33 (3H, m), 1.94- 1.78 (4H,m), 1.03 (6H, d). N-(propan-2-yl)-1-[2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperidine-4- carboxamide 56 [A001] A

Method 1: RT: 2.42 min, MI: 336.18 [M + H] (1H, 300 MHz, d6-dmso) 9.27(1H, s), 8.76 (2H, dd), 8.60 (1H, d), 8.33 (2H, dd), 7.98 (1H, d), 6.11(2H, s), 4.02-3.99 (4H, m), 3.60-3.56 (4H, m). 4-[2-(pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine-1- carboxamide 57 [A001] A

Method 1: RT: 4.8 min, MI: 418.47 [M + H] (1H, 300 MHz, d6-dmso) 9.25(1H, s), 8.76 (2H, d), 8.58 (1H, d), 8.31 (2H, d), 7.96 (1H, d), 6.27(1H, d), 4.00 (4H, m), 3.57 (4H, m), 3.47-3.38 (1H, m), 1.77- 1.66 (4H,m), 1.56 (1H, d, br), 1.25-1.04 (5H, m). N-cyclohexyl-4-[2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine-1- carboxamide 58 [A003] B

Method 1: RT: 0.64 min, MI: 362.18 [M + H] (1H, 300 MHz, CDCl₃) 9.03(1H, s), 8.81-7.79 (2H, m), 8.36-8.34 (1H, m), 8.24 (1H, s), 4.38-4.34(1H, m), 4.16-4.12 (4H, m), 3.42-3.33 (1H, m), 3.28- 3.19 (2H, m),3.09-3.02 (2H, m), 2.60-2.58 (2H, m). 2-{4-[5-methoxy-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]piperazin-2- yl}acetonitrile 59 [A001]A

Method 1: RT: 3.3 min, MI: 361 [M + H] (1H, 300 MHz, d6-dmso) 9.31 (1H,s), 8.80-8.78 (2H, m), 8.63 (1H, d), 8.32-8.30 (2H, m), 7.97 (1H, d),4.54 (1H, d), 4.25 (1H, d), 3.78-3.56 (3H, m), 3.18- 3.06 (2H, m),2.96-2.90 (2H, m). 1-[2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]-3-(trifluoromethyl)piper- azine 60 [A005] B

Method 1: RT: 4.43 min, MI: 395 [M + H] 1-[8-chloro-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4-yl]-3- (trifluoromethyl)piper- azine 61[A001] A

Method 1: RT: 1.30 min, MI: 321 [M + H] (1H, 300 MHz, d6-dmso) 9.33 (s,1H), 8.78 (d, 2H), 8.65 (d, 1H), 8.33 (d, 2H), 8.01 (d, 1H), 4.55-4.66(m, 1H), 3.73 (t, 1H), 3.28-3.47 (m, 4H), 1.66-1.75 (m, 2H), 1.04 (t,3H). (3S)-3-ethyl-1-[2- (pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]piperazine 62 [A001] A

Method 1: RT: 1.76 min, MI: 335 [M + H] (1H, 300 MHz, d6-dmso) 9.21-9.25(m, 1H), 8.71-8.77 (m, 2H), 8.54-8.60 (m, 1H), 8.22-8.29 (m, 2H),7.82-7.89 (m, 1H), 4.44- 4.62 (m, 2H), 3.31-3.44 (m, 2H), 3.01-3.15 (m,2H), 2.90 (t, 1H), 2.73 (brs, 1H), 1.68-1.79 (m, 1H), 1.00 (d, 6H).(3S)-3-(propan-2-yl)- 1-[2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]piperazine 63 [A008] B

Method 1: RT: 2.19 min, MI: 341.14 [M + H] (1H, 300 MHz, d4-MeOH) 8.89(1H, s), 8.61 (1H, d), 8.54 (1H, d), 8.43 (1H, s), 8.35 (1H, s), 8.20(1H, dd), 4.16 (3H, s), 3.94 (4H, m), 3.36 (4H, m). 1-[2-(3-fluoropyridin-4-yl)-5- methoxypyrido[3,4- d]pyrimidin-4- yl]piperazine64 [A001] A

Method 1: RT: 0.66 min, MI: 333 [M + H] (1H, 300 MHz, d6-dmso) 9.27 (1H,s), 8.78-8.76 (2H, m), 8.59 (1H, d), 8.33-8.31 (2H, m), 7.94 (1H, d),4.67 (2H, dd), 3.47- 3.39 (1H, m), 3.18-3.10 (2H, m), 3.08-3.04 (1H, m),2.41-2.33 (1H, m), 2.21-2.09 (2H, m), 1.94- 1.83 (1H, m), 1.80-1.65 (2H,m), 1.48-1.35 (1H, m). 4-{4-[(8aR)- octahydropyrrolo[1,2- a]piperazin-2-yl]pyrido[3,4- d]pyrimidin-2- yl}pyridine 65 [A004] B

Method 1: RT: 1.89 min, MI: 311.15 [M + H] (1H, 300 MHz, d6-dmso) 9.28(1H, s), 8.73 (1H, d), 8.65 (1H, d), 8.60 (1H, d), 8.13 (1H, dd), 8.00(1H, d), 4.06 (4H, m), 3.22 (4H, m), 2.97 (1H, s, br). 1-[2-(3-fluoropyridin-4- yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine 66 [A004] B

Method 1: RT: 4.02 min, MI: 379.15 [M + H] (1H, 300 MHz, d6-dmso) 9.27(1H, s), 8.73 (1H, d), 8.64 (1H, d), 8.60 (1H, d), 8.11 (1H, dd), 7.97(1H, dd), 4.53 (1H, dd), 4.21 (1H, d), 3.75 (1H, m), 3.66 (1H, td), 3.51(1H, dd), 3.15 (1H, d), 3.03 (1H, d), 2.88 (1H, t). 1-[2-(3-fluoropyridin-4- yl)pyrido[3,4- d]pyrimidin-4-yl]-3-(trifluoromethyl)piper- azine 67 [A001] A

Method 1: RT: 4.32 min, MI: 333.18 [M + H] (1H, 300 MHz, d6-dmso) 9.27(1H, s), 8.78-8.76 (2H, m), 8.59 (1H, d), 8.33-8.31 (2H, m), 7.94 (1H,d), 4.64 (1H, dd), 3.46 (1H, br t), 3.20-3.03 (3H, m), 2.41 (1H, br m),2.18 (2H, br m), 1.94-1.04 (1H, br m), 1.78-1.68 (2H, br m), 1.49-1.36(1H, m). 4-{4-[(3aS)- octahydo-1H- pyrrolo[3,2- c]pyridin-5-yl]pyrido[3,4- d]pyrimidin-2- yl}pyridine 68 [A005] B

Method 1: RT: 3.05 min, MI: 417 [M + H] (1H, 300 MHz, d6-dmso) 7.79 (d,2H), 7.53 (brs, 1H), 7.39 (d, 1H), 7.26 (d, 2H), 6.83 (d, 1H), 6.57-6.67(m, 5H), 3.83 (dd, 1H), 3.04 (t, 1H), 2.82-2.93 (m, 1H), 2.68 (d, 1H),2.59 (d, 1H), 2.35 (dd, 1H), 2.14 (dd, 1H). (3S)-3-benzyl-1-[8-chloro-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine 69[A001] A

Method 1: RT: 2.32 min, MI: 369 [M + H] (1H, 300 MHz, d6-dmso) 9.23 (s,1H), 8.74 (d, 2H), 8.56 (d, 1H), 8.26 (d, 2H), 7.89 (d, 1H), 7.51 (d,2H), 7.25-7.40 (m, 3H), 4.51 (dd, 2H), 3.95 (d, 1H), 3.34- 3.46 (m, 1H),3.13-3.24 (m, 2H), 2.97-3.03 (m, 1H). 3-phenyl-1-[2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine 70 [A003] B

Method 1: RT: 2.47 min, MI: 324.18 [M + H]; (1H, 300 MHz, CDCl₃) 9.00(1H, s), 8.76 (2H, d), 8.33 (2H, d), 8.20 (1H, s), 4.08 (3H, s), 3.89(4H, t), 3.77 (4H, t). 4-[5-methoxy-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]morpholine 71 [A001] A

Method 1: RT: 2.72 min, MI: 317.26 [M + H] (1H, 300 MHz, d4-MeOH) 9.24(1H, s), 8.69 (2H, dd), 8.54 (1H, d), 8.42 (2H, dd), 7.97 (1H, dd), 4.20(1H, dd), 4.07-3.92 (4H, m), 3.36-3.29 (1H, m), 3.00-2.94 (1H, m), 2.80(1H, d), 2.65 (1H, s, br). 3-ethynyl-1-[2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperazine 72 [A003] B

Method 1: RT: 5.36 min, MI: 414.22 [M + H] (1H, 300 MHz, d6-dmso) 8.82(1H, s), 8.71 (2H, dd), 8.27 (1H, s), 8.10 (2H, dd), 7.34-7.28 (5H, m),4.27 (1H, d), 4.04 (1H, d), 3.95-3.91 (1H, m), 3.91 (3H, s), 3.81-3.73(1H, m), 3.59-3.52 (1H, m), 3.38-3.33 (1H, m), 3.04-2.96 (1H, dd),2.91-2.75 (2H, m). 2-benzyl-4-[5- methoxy-2-(pyridin- 4-yl)pyrido[3,4-d]pyrimidin-4- yl]morpholine 73 [A005] B

Method 1: RT: 3.33 min, MI: 330 [M + H] {1-[8-chloro-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- yl]azetidin-3- yl}methanol 74 [A003] B

Method 1: RT: 1.88 min, MI: 431.18 [M + H] (3R)-3-[fluoro(phenyl)methyl]- 1-[5-methoxy-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperazine 75 [A005] B

Method 1: RT: 3.73 min, MI: 342 [M + H] (1H, 300 MHz, d6-dmso) 8.78 (d,2H), 8.35 (d, 1H), 8.33 (d, 2H), 7.89 (d, 1H), 4.88 (d, 1H), 4.21-4.27(m, 2H), 3.85-3.91 (m, 1H), 3.64-3.72 (m, 2H), 1.93-1.99 (m, 2H),1.57-1.65 (m, 2H). 1-[8-chloro-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperidin-4-ol 76 [A003] B

Method 1: RT: 2.08 min, MI: 431.14 [M + H] (1H, 500 MHz, d6-dmso) 8.81(1H, s), 8.71 (2H, d), 8.28 (1H, s), 8.10 (2H, d), 7.46-7.45 (5H, m),5.51 (1H, dd), 4.41 (1H, d, br), 4.02 (1H, m, br), 3.98 (3H, s), 3.20(2H, t, br), 3.08 (1H, d), 2.99 (1H, d), 2.68 (1H, t). (3R)-3-[fluoro(phenyl)methyl]- 1-[5-methoxy-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperazine 77 [A003] B

Method 1: RT: 2.08 min, MI: 447.08 [M + H] (3:1 mixture ofdiastereomers) (1H, 500 MHz, d6-dmso) 8.79 (0.25H, s), 8.77 (0.75H, s),8.70 (2H, dd), 8.27 (0.25H, s), 8.22 (0.75H, s), 8.11 (0.75H, d), 8.08(0.25H, d), 7.99 (1H, d, br), 7.43 (2H, t, br), 7.23 (1.5H, t), 7.20(0.5H, t), 5.65 (0.75H, d), 5.54 (0.25H, d), 4.54 (0.25H, t), 4.43(0.75H, t), 3.99 (0.75H, s), 3.93 (2.25H, s), 3.22 (0.75H, t), 3.14(0.25H, t), 3.94-2.92 (2H, m), 2.85 (1H, t), 2.74 (1H, m), 2.65 (1H, t).(4- fluorophenyl)[(2R)- 4-[5-methoxy-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperazin-2- yl]methanol

Synthesis of (S)—N²,N²-Dimethyl-3-phenyl-propane-1,2-diamine [A009]

Synthesis of[(S)-1-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-phenyl-ethyl]-carbamicacid tert-butyl ester [A010]

A mixture of Boc-L-phenylalaninol (25 g, 99.5 mmol), triphenylphosphine(31.3 g, 119.4 mmol), phthalimide (16.1 mg, 109.5 mmol) and THF (300 mL)was chilled to 0° C. A solution of diisopropyl azodicarboxylate (19.5mL, 99.5 mmol) in THF (100 mL) was added over 15 mins. The resultingpale yellow solution was allowed to return to room temperature overnight. The reaction mixture was concentrated to approximately 100 mLthen partitioned between ethyl acetate and water. A white precipitateformed which was collected by filtration. The organic layer was washedwith more water (×1) then brine (×1), dried (MgSO₄), filtered andevaporated to yield the title compound as a second white solid and thiswas material was used in further reactions, without further analysis.

Synthesis of ((S)-1-Aminomethyl-2-phenyl-ethyl)-carbamic acid tert-butylester [A011]

A mixture of[(S)-1-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-phenyl-ethyl]-carbamicacid tert-butyl ester [A010](2 g, 5.25 mmol), 4M HCl in dioxane (5 mL,20 mmol) and methanol (50 mL) was stirred at room temperature. Thereaction mixture was loaded straight on to a methanol conditioned SCX-2cartridge. The cartridge was washed with methanol (2col cols) and theneluted with 2N ammonia in methanol (2CV). LCMS analysis showed thetarget material to be predominantly in the methanol wash but alsopartially in the NH3 elution. The collected fractions were left to standfor a 3 days. After this time, needle like crystals started to form inthe methanol fraction. The crystals were collected by filtration anddried in the vac oven to yield the title compound [A011] (400 mg): NMR:(1H, 300 MHz, d6-DMSO) 8.08 (2H, br s), 7.04 (4H, s), 7.35-7.29 (4H, m),7.26-7.17 (1H, m), 3.83-3.66 (2H, m), 3.61 (1H, dd), 3.06 (1H, dd), 2.86(1H, dd);

LCMS method: 1, RT:2.50 min, MI 281 [M+H]

Synthesis of 2-((S)-2-Dimethylamino-3-phenyl-propyl)-isoindole-1,3-dione[A012]

A mixture of 2-((S)-2-Amino-3-phenyl-propyl)-isoindole-1,3-dione[A011](200 mg, 0.71 mmol), formaldehyde (2 mL, xs) and formic acid (2mL, xs) was heated to 100° C. for 2 hours. The reaction mixture wasconcentrated under vacuum then partioned between 2M K₂CO₃ and DCM. Theorganic layer was washed with water then brine, passed through a phaseseparator and evaporated to yield the title compound [A012] (200 mg)which was used without further purification: LCMS method: 1, RT: 2.42min, MI 309 [M+H]

Synthesis of (S)—N²,N²-Dimethyl-3-phenyl-propane-1,2-diamine [A009]

A solution of2-((S)-2-Dimethylamino-3-phenyl-propyl)-isoindole-1,3-dione [A012] (350mg), hydrazine monohydrate (66.1 ul, 1.36 mmol) and methanol (50 mL) wasstirred at room temperature for 20 hours. The solvent was removed undervacuum to yield a white solid. This was then partitioned between 10%citric acid and isopropanol. The aqueous layer was filtered, basifiedwith 2M NaOH, extracted into isoropanol, washed with brine, passedthrough a phase separator and evaporated to yield title compound [A009](93 mg): LCMS method: 1, RT:0.53 min, MI 179 [M+H]

Synthesis of ((S)-1-Methylaminomethyl-2-phenyl-ethyl)-carbamic acidtert-butyl ester [A013]

Synthesis of Synthesis ofToluene-4-sulfonicacid(S)-2-tert-butoxycarbonylamino-3-phenyl-propylester [A014]

To a solution of Boc-L-phenylalaninol (0.5 g, 1.989 mmol) in DCM (10 mL)at 0° C. was added triethylamine (0.83 mL, 5.968 mmol). The reactionmixture was stirred at this temperature for 5 minutes.para-Toluenesufonyl chloride (2.188 mmol, 0.42 g) was added dropwise asa solution in DCM (5 mL), and the reaction mixture was allowed to warmup to room temperature slowly. The reaction mixture stirred at roomtemperature for 4 hours. The reaction mixture was diluted with DCM (20mL) and washed with water. Layers separated and the organic layer driedover anhydrous magnesium sulphate. The DCM was evaporated to drynessunder reduced pressure to afford the title compound [A014] as a clearoil (0.8 g). No further purification was carried out and the crudeproduct was used immediately in the next step.

Synthesis of ((S)-1-Methylaminomethyl-2-phenyl-ethyl)-carbamic acidtert-butyl ester [A013]

Toluene-4-sulfonicacid(S)-2-tert-butoxycarbonylamino-3-phenyl-propylester [A014](0.80 g, 1.973 mmol) was dissolved in THF (10 mL) and methylamine (2N in THF, 10 mL) was added in one portion. The reaction mixturewas stirred at 60° C. overnight. The mixture was diluted with ethylacetate and washed with brine. The layers were separated and the ethylacetate dried over anhydrous magnesium sulphate. The solvent was removedunder reduced pressure to afford the title compound [A013] as a clearoil. No further purification was carried out at this stage. Crudematerial was used directly in subsequent reactions without furtherpurification.

Synthesis of (2S,4S)-4-Amino-2-hydroxymethyl-pyrrolidine-1-carboxylicacid tert-butyl ester [A015]

Synthesis of (2S,4R)-4-Methanesulfonyloxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester [A016]

N-Boc-trans-4-hydroxy-L-proline methyl ester (12.28 mmol, 3 g), wasdissolved in DCM (30 mL) and triethylamine (13.45 mmol, 1.87 mL) wasadded. The reaction was cooled to 0° C. and methanesulfonyl chloride(24.46 mmol, 1.89 mL) was added dropwise over 5 minutes. The reactionmixture was allowed to stir at this temperature for 45 minutes and thenwarmed to room temperature for 2 hours. Brine was added and the layerswere separated, the aqueous was extracted with dichloromethane (×2). Theorganics were washed with brine (×1), dried with MgSO₄, filtered andevaporated to yield the title compound as a clear oil (3.95 g): NMR (1H,300 MHz, CDCl₃): 5.22 (m, 1H), 4.39 (m, 1H), 3.74 (s, 3H), 3.73 (m, 2H),3.65 (s, 3H), 3.07 (s, 3H), 2.51 (m, 1H), 2.22 (m, 2H), 1.41 (d, 9H)

Step 2: Synthesis of (2S,4S)-4-Azido-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester [A017]

(2S,4R)-4-Methanesulfonyloxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester [A016](12.28 mmol, 3.95 g), wasdissoved in anhydrous DMF (20 mL) and sodium azide (61.14 mmol, 3.97 g)was added in one portion. The reaction was heated to 80° C. for 3 hours.Upon cooling the reaction mixture was quenched with water and extractedwith ethyl acetate (×3). The organics were washed with brine, dried withMgSO₄, filtered and evaporated to a colourless oil. Purified by flashcolumn chromatography using 0 to 40% EtOAc/cyclohexane to yield thetitle compound [A017] (2.24 g): NMR (1H, 300 MHz, CDCl₃): 4.36 (m, 1H),4.13 (m, 1H), 3.74 (s, 3H), 3.67 (m, 1H), 3.48 (dt, 1H), 2.47 (m, 1H),2.14 (m, 2H), 1.43 (d, 9H)

Synthesis of (2S,4S)-4-Amino-2-hydroxymethyl-pyrrolidine-1-carboxylicacid tert-butyl ester [A015]

Water (5 mL) was added to a stirred solution of(2S,4S)-4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester [A017](4.44 mmol, 1.2 g) and triphenylphosphine (9.32mmol 2.45 g), in toluene (40 mL) and the reaction was heated to 60° C.overnight. Upon cooling water was added and the layers separated. Theaqueous was basified with 2M NaOH added and extracted twice with ethylacetate, the organics combined, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to give the title compound (200 mg): NMR (1H, 300MHz, CDCl₃): 4.20 (m, 1H), 3.71 (s, 3H), 3.62 (m, 1H), 3.50 (m, 1H),3.22 (m, 1H), 2.43 (m, 1H), 1.78 (m, 1H), 1.43 (d, 9H)

Synthesis of ((1R,2R)-1-Aminomethyl-2-fluoro-2-phenyl-ethyl)-carbamicacid tert-butyl ester [A018]

Synthesis of ((1R,2R)-2-Hydroxy-1-hydroxymethyl-2-phenyl-ethyl)-carbamicacid tert-butyl ester [A019]

(1R,2R)-(−)-2-Amino-1-phenyl-propane-1,3-diol (5.98 mmol, 1.0 g) wasdissolved in methanol (10 mL) and cooled to 0° C. A solution ofdi-tert-butyl dicarbonate in methanol (4 mL) was added and the reactionwas warmed to room temperature and stirred for 2 hours. The solvent wasremoved in vacuo and the product was purified by flash chromatographyeluting with 0 to 70% EtOAc/cyclohexane to yield the title compound[A019] (1.20 g): NMR (1H, 300 MHz, CDCl₃): 7.29 (m, 5H), 5.19 (m, 1H),4.96 (m, 1H), 3.35 (m, 1H), 2.66 (m, 1H), 1.33 (s, 9H); LCMS method: 1,RT:4.35 min, MI: no trace.

Synthesis of ((1R,2R)-2-Hydroxy-1-hydroxymethyl-2-phenyl-ethyl)-carbamicacid tert-butyl ester [A020]

Allyl chloroformate (11.222 mmol, 1.35 g) was added dropwise to astrirred solution of((1R,2R)-2-Hydroxy-1-hydroxymethyl-2-phenyl-ethyl)-carbamic acidtert-butyl ester [A019](1.20 g, 4.48 mmol) and pyridine (15.711 mmol,1.27 mL) in DCM (50 mL) at 0° C. The reaction was allowed to warm toroom temperature and stirred for an hour. Water was added and the layersseparated. The aqueous was extracted twice with DCM. The organics werecombined, washed with brine, dried over anhydrous MgSO4, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography using 0 to 100% EtOAc/cyclohexane to yield the titlecompound [A020] (0.93 g): NMR (1H, 300 MHz, CDCl₃): 7.28 (m, 5H), 5.91(m, 1H), 5.34 (d, 1H), 5.27 (d, 1H), 4.99 (m, 1H), 4.84 (t, 1H), 4.61(d, 2H), 4.27 (dd, 1H), 4.07 (dd, 1H), 4.01 (m, 1H), 3.09 (bs, 1H), 1.33(s, 9H); LCMS: LC-MS17QC 94% 352+[M+H]5.17 min

Synthesis of Carbonic acid allyl ester(2R,3R)-2-tert-butoxycarbonylamino-3-phenyl-3-(tetrahydro-pyran-2-yloxy)-propylester [A021]

A solution of((1R,2R)-2-Hydroxy-1-hydroxymethyl-2-phenyl-ethyl)-carbamic acidtert-butyl ester [A020](1.42 mmol, 0.50 g) and DIPEA (4.97 mmol 0.865mL) in DCM (20 mL) was added dropwise to a solution of(diethylamino)sulfur trifluoride (DAST) (4.97 mmol, 0.610 mL) at −78° C.under nitrogen. The reaction was slowly warmed to room temperature andstirred for 2 hours. Water was added then extracted twice with DCM. Theorganics were combined, washed with brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo to yield the title compound [A021]which was was used directly in the next step without furtherpurification: LCMS method: 1, RT:3.27 min, MI not seen.

Synthesis of ((1R,2R)-2-Fluoro-1-hydroxymethyl-2-phenyl-ethyl)-carbamicacid tert-butyl ester [A022]

To a solution of carbonic acid allyl ester(2R,3R)-2-tert-butoxycarbonylamino-3-fluoro-3-phenyl-propyl ester[A021](2.0 mmol, 0.71 g) in anhydrous THF (15 mL) under nitrogen, wasadded tetrakis(triphenylphosphine)palladium(0) (0.08 mmol 0.093 g) andmorpholine (3.014 mmol, 0.26 mL). The reaction was stirred at rt for 1hunder a nitrogen atmosphere. Brine was added and the mixture extractedtwice with ethyl acetate. The organics were combined, dried over MgSO₄,filtered and concentrated in vacuo. The product was purified by flashchromatography using 0 to 10% MeOH/DCM to yield the title compound[A022] (0.19 g): NMR (1H, 300 MHz, CDCl₃): 7.32 (m, 5H), 5.68 (d, 1H),5.11 (m, 1H), 3.99 (m, 1H), 3.86 (m, 1H), 3.67 (m, 1H), 1.39 (s, 9H)

Synthesis of[(1R,2R)-1-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-fluoro-2-phenyl-ethyl]-carbamicacid tert-butyl ester [A023]

A solution of ((1R,2R)-2-Fluoro-1-hydroxymethyl-2-phenyl-ethyl)-carbamicacid tert-butyl ester [A022](0.705 mmol, 0.19 g), triphenylphosphine(0.988 mmol, 0.259 g) and phthalimide (0.988 mmol, 0.145 g) was cooledto 0° C. and diisopropyl azodicarboxylate (DIAD) (0.988 mmol, 0.193 mL)was added dropwise. The reaction was allowed to warm to room temperatureand stirred for 1 hour. The solvent was removed in vacuo and the residuewas dissolved in DCM. 2M NaOH (aqueous solution) was added and thelayers separated using a phase separator. The organic was concentratedin vacuo. The product was purified by flash chromatography using 0 to30% EtOAc/cyclohexane to yield the title compound [A023] (0.28 g):1LCMS1; 98%, 399.15+[M+H]+, 5.45 min; NMR (1H, 300 MHz, CDCl3): 7.80 (m,2H), 7.65 (m, 2H), 7.40 (m, 4H), 7.31 (m, 1H), 5.72 (dd, 1H), 5.06 (d,1h), 4.47 (m, 1H), 3.83 (dd, 1H), 3.57 (dd, 1H), 1.20 (s, 9H)

Synthesis of ((1R,2R)-1-Aminomethyl-2-fluoro-2-phenyl-ethyl)-carbamicacid tert-butyl ester [A018]

[(1R,2R)-1-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-fluoro-2-phenyl-ethyl]-carbamicacid tert-butyl ester [A023](0.705 mmol, 0.28 g) was dissolved inmethanol (5 mL) and Hydrazine monohydrate (0.916 mmol, 0.045 mL) wasadded. The reaction was stirred at room temperature for 1 hour then at60° C. overnight. Upon cooling the solvent was removed in vacuo and theresidue dissolved in DCM. 2M NaOH (aqueous solution) was added and themixture extracted twice. The organics were combined, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. The product waspurified using an SCX-2 cartridge, applying the crude material as a DCMsolution and washing with methanol and DCM. The material was then washedoff the SCX-2 cartridge by washing with ammonia (2N in methanol) and theammonia washes concentrated in vacuo to yield the title compound [A018](0.12 g): NMR (1H, 300 MHz, CDCl₃): 7.34 (m, 5H), 5.62 (d, 1H), 5.19 (d,1H), 3.89 (m, 1H), 2.83 (m, 2H), 1.40 (s, 9H) Synthesis of2-Fluoromethyl-piperazine [A024]

(1,4-Dibenzyl-piperazin-2-yl)-methanol [A026]

A solution of 1,4-Dibenzyl-piperazine-2-carboxylic acid ethyl ester[A025](3.7 g, 10.9 mmol) in THF (10 mL) was added dropwise to asuspension of LiAlH₄ (2.24 g, 59 mmol) in THF (20 mL) at 0° C. Thereaction was warmed to room temperature and stirred overnight. Thereaction was diluted with ether, cooled to 0° C. and quenched with water(2.25 mL) and 2M NaOH (4.5 ml) and water (4.5 mL). The suspension wasstirred for 15 mins and anhydrous MgSO4 was added and stirred for afurther 15 mins. The white solid was filtered off (celite) and thesolvent removed in vacuo. The product was purified by flashchromatography using 0 to 100% EtOAc/cyclohexane to give the titlecompound [A026](3.03 g, 94% yield). LCMS method: 1, RT:2.16 min, MI297.23 [M+H];

NMR (1H, 300 MHz, CDCl₃): 3.43 (m, 3H), 2.63 (m, 3H), 2.95 (m, 1H), 3.49(m, 3H), 3.61 (d, 1H), 4.04 (dd, 2H), 7.31 (m, 10H)

1,4-Dibenzyl-2-fluoromethyl-piperazine [A027]

(1,4-Dibenzyl-piperazin-2-yl)-methanol [A026](1.09 g, 3.6 mmol) in DCM(5 mL) was added dropwise to a stirred solution of DAST (0.9 mL, 7.35mmol) in DCM (10 mL) at 0° C. The reaction was warmed to roomtemperature and stirred overnight. Aqueous 2M NaOH (10 mL) was added thethe layers seperated by phase seperator. The solvent was removed invacuo and the product was purified by flash chromatography using 0 to30% EtOAc/cyclohexane to give the title compound [A027](0.42 g, 38%yield). LCMS method: 1, RT:5.88 min, MI 299.38 [M+H]; NMR (1H, 300 MHz,CDCl₃): 2.28 (m, 3H), 2.50 (m, 2H), 2.70 (m, 2H), 2.83 (m, 1H), 3.49 (m,3H), 4.11 (d, 1H), 4.53 (ddd, 1H), 4.68 (ddd, 1H), 7.25 (m, 10H)

2-Fluoromethyl-piperazine [A024]

1,4-Dibenzyl-2-fluoromethyl-piperazine [A027](0.32 g, 1.07 mmol) wasdissolved in DCE (10 mL) and 1-Chloroethyl chloroformate (0.35 mL, 3.21mmol) was added. The reaction was heated to reflux overnight. Uponcooling the solvent was removed in vacuo and the intermediatedicarabamate was purified by flash chromatpgraphy eluting with 0 to 50%EtOAc/cyclohexane. The residue was dissolved in methanol (10 mL) andheated to reflux for 1 hour. The solvent was removed in vacuo to givethe title compound [A024] which was used in the next step and usedwithout further purification

Synthesis of Piperazin-2-yl-acetonitrile [A028]

(1,4-Dibenzyl-piperazin-2-yl)-acetonitrile [A029]

A solution of (1,4-Dibenzyl-piperazin-2-yl)-methanol [A026](1 g, 3.37mmol) in DCM (10 mL) was added dropwise to a solution of thionylchloride (0.32 mL, 4.4 mmol) in DCM (5 mL) and the reaction was stirredat room temperature ovenight. The solvent was removed in vacuo and waterwas added. The aqeous was extracted with ether then bascified withsaturated Na2CO3. This was extracted twice with DCM, dried overanhydrous MgSO4, filtered and concentrated in vacuo and used crude inthe next step and used without further purification.

To a refluxing solution of KCN (0.244 g, 3.7 mmol) in water (10 mL) wasadded 1,4-Dibenzyl-2-chloromethyl-piperazine (0.91 g, 2.9 mmol) inethanol (10 mL) dropwise. The reaction was heated to reflux for 3 hours.Upon cooling the solvent was removed in vacuo and the residue was wastaken up in DCM, washed with water, dried over MgSO4, filtered andconcentrated in vacuo. The product was purified by flash chromatographyusing 0 to 40% EtOAc/cyclohexane, to give the title compound [A029](0.52g, 59% yield). LCMS method: 1, RT:2.87 min, MI 306.26 [M+H];

NMR (1H, 300 MHz, CDCl₃): 2.43 (m, 3H), 2.58 (m, 4H), 2.87 (dd, 1H),3.00 (m, 1H), 3.48 (m, 3H), 3.80 (d, 1H), 7.28 (m, 10H).

Piperazin-2-yl-acetonitrile [A028]

(1,4-Dibenzyl-piperazin-2-yl)-acetonitrile [A029](0.52 g, 1.7 mmol) wasdissolved in DCE (10 mL) and 1-Chloroethyl chloroformate (0.55 mL, 5.1mmol) was added. The reaction was heated to reflux for 2 days. Uponcooling the solvent was removed in vacuo and the intermediatedicarabamate was purified by flash chromatography eluting with 0 to 40%EtOAc/cyclohexane. The residue was dissolved in methanol (10 ml) andheated to reflux for an hour. The solvent was removed in vacuo to giveclean product. NMR (1H, 300 MHz, d6-dmso): 3.16 (m, 3H), 3.03 (t, 1H),3.49 (m, 4H), 3.89 (m, 1H), 10.06 (m, 2H)

Synthesis of 2-Ethynyl-piperazine [A030]

Synthesis of (R)-2-Hydroxymethyl-piperazine-1,4-dicarboxylic aciddi-tert-butyl ester [A031]

To a stirred solution of (R)-1-Boc-2-Hydroxymethyl-piperazine (1 g, 4.62mmol) and Na₂CO₃ (990 mg, 9.25 mmol) in a mixture of dioxane (8 ml) andwater (2 ml) at 0 OC was added Di-tert-butyl dicarbonate and thereaction mixture warmed to room temperature. After 18 hours all solventswere removed in vacuo and the resulting residue partitioned between DCMand water. The DCM phase was passed through phase separation cartridgeand evaporated to provide a white solid. Purification by columnchromatography (0-50% EtOAc:cyclohexane) gave the title compound [A031]as a white solid (1.26 g, 86%). 1H-NMR (1H, 300 MHz, CDCl₃): 4.17 (2H,s, br), 3.93 (1H, s, br), 3.84 (1H, d, br), 3.59 (2H, s, br), 2.95 (3H,s, br), 1.46 (18H, s).

Synthesis of 2-Formyl-piperazine-1,4-dicarboxylic acid di-tert-butylester [A032]

A solution of oxalyl chloride (165 μl, 1.90 mmol) in DCM (5 ml) wascooled to −78° C. DMSO (270 μl, 3.79 mmol) was added dropwise and thereaction mixture stirred for 15 mins. A solution of(R)-2-Hydroxymethyl-piperazine-1,4-dicarboxylic acid di-tert-butyl ester[A031](500 mg, 0.58 mmol) in DCM (1 ml) was added dropwise and thereaction mixture stirred for 1 hour. Triethylamine (1.1 ml, 7.90 mmol)was added and the reaction mixture warmed to room temperature. SaturatedNaHCO₃ was added, the layers separated and the organic phase collectedand evaporated to give the title compound [A032] as a white powder (480mg, 97%). 1H-NMR (1H, 300 MHz, CDCl₃): 9.58 (1H, s), 4.63-4.45 (2H, m,br), 3.95-3.79 (2H, m, br), 3.15-3.11 (2H, m, br), 2.88 (1H, d, br),1.44 (18H, s).

Synthesis of 2-Ethynyl-piperazine-1,4-dicarboxylic acid di-tert-butylester [A033]

To a stirred solution of 2-Formyl-piperazine-1,4-dicarboxylic aciddi-tert-butyl ester [A032](480 mg, 0.530 mmol) and K₂CO₃ (425 mg, 3.06mmol) in MeOH (20 ml) was added Dimethyl(1-diazo-2-oxopropyl)phosphonate (350 mg, 1.83 mmol). After 18 hours thesolvent was removed in vacuo and the resulting residue partitioned(DCM:water). The organic phase was separated and concentrated to providethe title compound [A033] as a white solid (430 mg, 91%).1H-NMR (1H, 300MHz, CDCl₃): 4.88 (1H, s, br), 4.25-4.01 (2H, m, br), 3.80 (1H, d, br),3.18 (1H, t, br), 3.02-2.74 (2H, m), 2.23 (1H, d), 1.47 (18H, s).

Synthesis of 2-Ethynyl-piperazine [A030]

2-Ethynyl-piperazine-1,4-dicarboxylic acid di-tert-butyl ester[A033](430 mg, 1.39 mmol) was stirred in 4N HCl:dioxane (1 ml) for 4hours. A pale yellow solid (226 mg, 89%) was collected by filtration andwashed with Et₂O then dried in a vacuum oven at 40 OC to yield the titlecompound [A030]: 1H-NMR (1H, 300 MHz, d6-dmso): 4.57 (1H, dt), 4.04 (1H,d), 3.63 (1H, dd), 3.42-3.23 (5H, m).

Synthesis of 2-Benzyl-morpholine [A034]

Synthesis of 1-Chloro-3-phenyl-propan-2-ol [A035]

To a stirred solution of Phenyl magnesium bromide (3M in Et₂O, 4.4 ml,13 mmol) in Et₂O (14 ml) at 0° C. was added CuI (210 mg, 1.08 mmol).Epichlorohydrin (1 g, 10.8 mmol) in Et₂O (14 ml) was then added and thereaction mixture allowed to warm to room temperature then stirred for 2hours. Sat. NH₄Cl was added and the solution diluted with water thenextracted with EtOAc (×2). The combined organics were washed with brine,dried over MgSO₄ and concentrated. Purification by column chromatography(0-20% Et₂O:cyclohexane) provided the title compound [A035] as acolourless oil (1.66 g, 90%). 1H-NMR (1H, 300 MHz, CDCl₃): 7.36-7.22(5H, m), 4.11-4.01 (1H, m), 3.59 (1H, dd), 3.50 (1H, dd), 2.90 (2H, d),2.18 (1H, d).

Synthesis of 2-Benzyl-morpholine [A034]

To a stirred solution of NaOH (1.63 g, 40.8 mmol) in water3.5 ml) wasadded 1-Chloro-3-phenyl-propan-2-ol [A035](1.16 g, 6.8 mmol) in MeOH (7ml). After 5 min 2-Aminoethane hydrogen sulphate (3.84 g, 27.2 mmol) wasadded and the reaction mixture stirred at 40 OC for 2 hours. NaOH(powdered, 1.63 g, 40.8 mmol) and PhMe (18 ml) were then added and thereaction heated to 65° C. for 18 hours. Dilution with water (10 ml), wasfollowed by extraction with PhMe (×2). The combined organics were washed(water then brine), dried and concentrated. Purification by columnchromatography (0-10% MeOH:DCM) provided the title compound as acolourless oil (360 mg, 30%). 1H-NMR (1H, 300 MHz, CDCl₃): 7.31-7.19(5H, m), 3.86 (1H, dd), 3.70-3.54 (2H, m), 2.92-2.77 (4H, m), 2.67-2.55(2H, m).

Synthesis of (R)-2-(Fluoro-phenyl-methyl)-piperazine [A036]

Synthesis of (R)-Piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butylester 2-methyl ester [A037]

To a stirred suspension of (R)-1-N-Boc-piperazine-2-carboxylic acidmethyl ester hydrochloride (2 g, 7.12 mmol) and Na₂CO₃ (2.26 g, 21.4mmol) in dioxane (16 ml) and water (4 ml) at 0° C. was addedDi-tert-butyl-dicarbonate (1.55 g, 7.12 mmol). After 18 hours allsolvents were removed in vacuo and the resulting residue partitionedbetween DCM and water. The organic phase was collected and evaporated togive a colourless oil. Purification by column chromatography (0-30%EtOAc:cyclohexane) gave the title compound [A037] as a white powder(2.33 g, 95%). 1H-NMR (1H, 300 MHz, CDCl₃): 5.30 (1H, s), 4.72 (1H, s,br), 4.54 (1H, t, br), 4.08-3.80 (1H, m), 3.73 (3H, s), 3.27-2.73 (3H,m), 1.44 (18H, s).

Synthesis of (R)-Piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butylester [A038]

(R)-Piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl ester 2-methylester [A037](2.33 g, 6.77 mmol) and KOH (1.14 g, 20.3 mmol) were heatedto reflux in EtOH (50 ml) for 18 hours. Having cooled to roomtemperature, solvents were removed in vacuo and the residue purified bycolumn chromatography (0-10% MeOH:DCM; 0.1% TEA) to provide the titlecompound [A038] as a pale orange foam (2.1 g, 94%). 1H-NMR (1H, 300 MHz,CDCl₃): 4.66-4.50 (2H, m, br), 3.96-3.74 (2H, m, br), 3.47 (1H, s), 3.23(1H, s, br), 2.85 (1H, s, br), 1.42 (18H, s).

Synthesis of(R)-2-(Methoxy-methyl-carbamoyl)-piperazine-1,4-dicarboxylic aciddi-tert-butyl ester [A039]

(R)-Piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl ester[A038](2.10 g, 6.36 mmol),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (2.9 g, 7.63 mmol), N,O-Dimethylhydroxylaminehydrochloride (750 mg, 7.6 3 mmol) and TEA (2.2 ml, 15.3 mmol) werestirred in DMA for 18 hours. The reaction mixture was then partitionedbetween EtOAc and NaOH (1M), and the aqueous phase re-extracted withEtOAc. The combined organics were dried over MgSO₄ and concentrated.Purification by column chromatography (0-50% EtOAc:cyclohexane) gave thetitle compound [A039] as a viscous pale yellow oil (2.15 g, 91%). 1H-NMR(1H, 300 MHz, CDCl₃): 5.30 (1H, s), 4.86-4.71 (1H, m), 4.47-4.32 (1H,m), 4.06-3.75 (2H, m), 3.85 (3H, s), 3.18 (3H, s), 3.18-2.85 (2H, m),1.45 (9H, s), 1.42 (9H, s). LCMS method: 1, RT:3.46 min, MI 374.26[M+H].

Synthesis of (R)-2-Benzoyl-Piperazine-1,4-Dicarboxylic AcidDi-Tert-Butyl Ester [A040]

To a stirred solution of(R)-2-(Methoxy-methyl-carbamoyl)-piperazine-1,4-dicarboxylic aciddi-tert-butyl ester [A039](500 mg, 1.34 mmol) in THF at 0° C. was addedPhenylmagnesium chloride solution (3.4 ml, 6.7 mmol, 2.0 M in THF) andthe reaction mixture allowed to warm to room temperature. Having stirredfor 4 hours the solution was quenched (1N NaOH) and solvents removed invacuo. The residue was partitioned between DCM and Rochelles salt (10%aq.) and the organic phase separated and aqueous re-extracted with DCM.The combined organics were then dried (MgSO₄) and concentrated.Purification by column chromatography (0-50% EtOAc:cyclohexane) providedthe title compound [A040] as a white solid (416 mg, 80%). 1H-NMR (1H,300 MHz, CDCl₃): 7.89 (2H, s, br), 7.57 (1H, s, br), 7.47 (2H, s, br),5.53 (0.6H, s, br), 5.35 (0.4H, s, br), 4.53-4.38 (1H, m, br), 4.06(0.6H, m, br), 3.87-3.80 (1.4H, m, br), 3.67-3.53 (1H, m, br), 3.41-3.29(1H, m, br), 2.94-2.81 (1H, m, br), 1.55-1.12 (19H, m, br); LCMS method:1, RT:3.75 min, MI 391.32 [M+H]

Synthesis of (R)-2-(Hydroxy-phenyl-methyl)-piperazine-1,4-dicarboxylicacid di-tert-butyl ester [A041]

To a stirred suspension of (R)-2-Benzoyl-piperazine-1,4-dicarboxylicacid di-tert-butyl ester [A040](220 mg, 0.553 mmol) in MeOH (4 ml) wasadded sodium borohydride (41 mg, 1.11 mmol). After 2 hours the reactionmixture was partitioned between EtOAc and water, the organic phaseseparated and concentrated in vacuo to give the title compound [A041] asa white crystalline solid (210 mg, 97%). 1H-NMR (1H, 300 MHz, CDCl₃):7.43-7.26 (5H, m), 4.74 (1H, s, br), 4.31-3.65 (4H, m), 3.25-2.81 (3H,m), 1.55-1.46 (18H, m), 1.13 (1H, s, br); LCMS method: 1, RT:3.86 min,MI 393.32 [M+H]

Synthesis of (R)-2-(Fluoro-phenyl-methyl)-piperazine-1,4-dicarboxylicacid di-tert-butyl ester [A042]

To a stirred solution of(R)-2-(Hydroxy-phenyl-methyl)-piperazine-1,4-dicarboxylic aciddi-tert-butyl ester [A041](210 mg, 0.535 mmol) in CHCl₃ (3 ml) at 0 OCwas added (Diethylamino)sulfur trifluoride (330 μl, 2.68 mmol). After 2hours the reaction mixture was quenched with ice, basified with NaHCO₃(to pH8), then the product extracted into DCM, which was evaporated togive a colourless oil. Purification was achieved by columnchromatography (0-50% EtOAc:cyclohexane) to provide the title compound[A042] as a white solid (85 mg, 40%). 1H-NMR (1H, 300 MHz, CDCl₃): 7.34(5H, m, br), 5.53 (1H, d, br), 4.38-3.84 (4H, m, br), 3.08-2.84 (3H, m,br), 1.49 (9H, s, br), 1.25 (9H, s, br); LCMS method: 1, RT:3.68 min, MI295.21 [M+H]

Synthesis of (R)-2-(Fluoro-phenyl-methyl)-piperazine [A036]

(R)-2-(Fluoro-phenyl-methyl)-piperazine-1,4-dicarboxylic aciddi-tert-butyl ester [A042](85 mg, 0.215 mmol) was stirred in 4NHCl:dioxane (2 ml). After 2 hours the solution was dissolved in MeOH andloaded onto an SCX cartridge which was washed with MeOH followed by 2NNH₃:MeOH. Evaporation provided the title compound [A036] as a yellow gum(35 mg, 83%). 1H-NMR (1H, 300 MHz, d4-MeOH): 7.49-7.43 (5H, m), 5.25(1H, d), 3.85 (1H, dd), 3.79-3.726 (1H, m), 3.20-3.14 (2H, m), 3.00-2.82(3H, m).

Synthesis of (4-Fluoro-phenyl)-(R)-piperazin-2-yl-methanol [A043]

Synthesis of (R)-2-(4-Fluoro-benzoyl)-piperazine-1,4-dicarboxylic aciddi-tert-butyl ester [A044]

To a stirred solution of(R)-2-(Methoxy-methyl-carbamoyl)-piperazine-1,4-dicarboxylic aciddi-tert-butyl ester [A043](1.15 g, 3.08 mmol) in THF (24 ml) was added4-Fluorophenylmagnesium bromide solution (2.0M in Et₂O, 7.7 ml, 15.4mmol) and the reaction mixture allowed to warm to room temperature.Having stirred for 4 hours the reaction was quenched (1N NaOH) andsolvents removed in vacuo. The residue was partitioned between DCM andRochelles salt (10% aq). The organic phase was separated and aqueousphase re-extracted with DCM. Evaporation of the combined organicsfollowed by purification by column chromatography (0-50%EtOAc:cyclohexane) gave the title compound [A044] as a pale yellow oil(800 mg, 64%). 1H-NMR (1H, 300 MHz, CDCl₃): 7.94 (2H, s, br), 7.15 (2H,s, br), 5.47 (1H, m, br), 4.48-4.32 (1H, m, br), 4.07-4.03 (1H, m, br),3.91-3.76 (1H, m, br), 3.61-3.51 (1H, m, br), 3.43-3.31 (1H, m, br),3.18-3.24 (1H, m, br), 1.56-1.17 (18H, m, br); LCMS method: 1, RT:3.79min, MI 409.32 [M+H]

Synthesis of(R)-2-[(4-Fluoro-phenyl)-hydroxy-methyl]-piperazine-1,4-dicarboxylicacid di-tert-butyl ester [A045]

To a stirred solution of(R)-2-(4-Fluoro-benzoyl)-piperazine-1,4-dicarboxylic acid di-tert-butylester [A044](520 mg, 1.28 mmol) in MeOH (8 ml) was added sodiumborohydride at 0 OC and the reaction mixture allowed to warm to roomtemperature. After 2 hours the reaction mixture was partitioned betweenEtOAc and water, the organic phase separated and concentrated in vacuoto give a pale yellow oil. Purification by column chromatography (0-50%EtOAc:cyclohexane) provided the title compound [A045] as a whitecrystalline solid (330 mg, 63%). 1H-NMR (1H, 300 MHz, CDCl₃): 7.41-7.08(5H, m), 4.74 (1H, m), 4.27-3.93 (3H, m), 3.64 (1H, m), 3.23-2.84 (1H,m), 1.45 (18H, m), 1.18 (1H, s, br).

Synthesis of (4-Fluoro-phenyl)-(R)-piperazin-2-yl-methanol [A043]

(R)-2-[(4-Fluoro-phenyl)-hydroxy-methyl]-piperazine-1,4-dicarboxylicacid di-tert-butyl ester [A045](330 mg, 0.808 mmol) was stirred in 4NHCl:dioxane (2 ml). After 2 hours the solution was dissolved in MeOH andloaded onto an SCX cartridge which was washed with MeOH followed by 2NNH₃:MeOH. Evaporation provided the title compound [A043] as a yellow gumwhich was used without further purification (170 mg, 100%).

Synthesis ofN—[(S)-1-Benzyl-2-(2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-formamide[78]

A mixture of(S)-3-Phenyl-N¹-(2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-propane-1,2-diamine[6](70 mg, 0.21 mmol) and ethylformate (1.5 mL, 18.6 mmol) was heated inthe microwave at 100° C. for 1 hour. The reaction mixture wasconcentrated under vacuum, redissolved in methanol then loaded onto amethanol conditioned SCX-2 cartridge (5 g). The cartridge was washedwith methanol (2ColVols) then eluted with 2N NH3 in methanol (2CV). Theammonia washes were evaporated to yield the title compound [78]: LCMSmethod: 1, RT:3.87 min, MI 385 [M+H];

NMR: (1H, 300 MHz, d6-dmso) 9.17 (1H, s), 8.90-8.87 (1H, br t), 8.73(2H, d), 8.63 (1H, d), 8.25 (2H, dd), 8.14 (1H, d), 8.04 (1H, br d),7.97 (1H, br s), 7.327.20 (5H, m), 4.55-4.46 (1H, m), 3.98-3.90 (1H, m),3.70-3.62 (1H, m), 3.00-2.93 (1H, dd), 2.85-2.77 (1H, dd)

Synthesis ofN—[(S)-1-Benzyl-2-(2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-acetamide[79]

To a stirred solution of(S)-3-Phenyl-N¹-(2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-propane-1,2-diamine[6](70mg, 0.21 mmol), DIPEA (73 ul, 0.42 mmol) and anhydrous DCM (5 mL) atroom temperature was added acetic anhydride (29 1, 0.31 mmol). Thereaction mixture was concentrated under vacuum then redissolved inmethanol plus formic acid (2 drops) and loaded onto a methanolconditioned SCX-2 cartridge (5 g). The cartridge was washed withmethanol (2CV) then eluted with 2N NH₃ in methanol (2CV). The ammoniawashes were evaporated to yield the title compound [79]: LCMS method: 1,RT:3.92 min, MI 399 [M+H]; NMR: (1H, 300 MHz, d6-dmso) 9.17 (1H, s),8.85 (1H, br t), 8.72 (2H, dd), 8.63 (1H, d), 7.85 (1H, dd), 7.30-7.17(5H, m), 4.43-4.33 (1H, m), 4.01-3.92 (1H, m), 3.63-3.55 (1H, m), 2.90(1H, dd), 2.80 (1H, dd), 1.70 (3H, s)

Synthesis ofmethyl[(2S)-1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-yl]amine[80]

A stirred suspension of lithium aluminium hydride (19 mg, 0.5 mmol) inanhydrous THF (2.5 mL) was chilled to 0° C.N—[(S)-1-Benzyl-2-(2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-formamide[78](40mg, 0.1 mmol) in THF (2.5 mL) was added over five minutes. The reactionmixture was allowed to warm to room temperature and stirred for 18 h. Afurther portion of lithium aluminium hydride (10.5 mg, 0.28 mmol) wasadded to the reaction mixture and stirring continued at room temperaturefor 18 hours. Another portion of lithium aluminium hydride (30 mg, 0.79mmol) was added to the reaction mixture and stirring continued at roomtemperature for a further 18 hours. This procedure was repeated on asecond batch ofN—[(S)-1-Benzyl-2-(2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-formamide[78](40mg, 0.234 mmol) and the crude reaction mixture combined and diluted withether (20 mL), cooled to 0° C. and quenched by drop-wise addition ofwater (approx 150 μL), NaOH (approx 300 μL of a 2M solution) and water(approx 300 μL of a 2M solution) again. MgSO₄ was added and the mixturefiltered and concentrated by rotary evaporation. The crude residue waspurified by preparative HPLC (method A). The appropriate fractions werecombined, the solvent evaporated and the residue was dissolved in MeODresulting in precipitation of an impurity which was removed byfiltration to give the title compound [80] (2.5 mg). LCMS method: 1,RT:2.39 min, MI 371 [M+H]. ¹H NMR (1H, 300 MHz, d6-dmso) 9.13 (1H, s),8.64-8.62 (2H, m), 8.54 (1H, d), 8.21-8.19 (2H, m), 7.99 (1H, d),7.32-7.21 (5H, m), 3.97-3.91 (1H, m), 3.78-3.71 (1H, m), 3.29-3.22 (1H,m), 3.05-2.99 (1H, m), 2.77-2.70 (1H, m).

Synthesis of(2S)-2-benzyl-4-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-1-methylpiperazine;formic acid [81]

A stirred solution of4-((S)-3-Benzyl-piperazin-1-yl)-5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine[30]in CH₂Cl₂ (2 mL) was prepared. Paraformaldehyde (55 mg), acetic acid (6mL, 0.121 mmol) and CNBH₃ (180 mg of MP-CNBH₃ with 2 mmol/g loading,0.360 mmol) were added and the reaction was shaken at room temperatureovernight. The resin was filtered off and the product was loaded onto aCSX cartridge, washing with methanol and eluting with ammonia inmethanol. The ammonia fraction was concentrated and the residue purifiedthen by prep LCMS. The appropriate fractions were combined andconcentrated to give the title compound [81]. LCMS method: 1, RT:2.74min, MI 427.22 [M+H]; ¹H NMR (1H, 300 MHz, CDCl₃) 8.95 (s, 1H),8.73-8.71 (d, 2H), 8.29 (s, 1H), 8.13-8.11 (d, 2H), 8.06 (s, 1H),7.37-7.35 (m, 3H), 7.22-7.19 (m, 2H), 4.28 (d, 1H), 4.07 (d, 1H), 3.82(s, 3H), 3.72-3.63 (m, 1H), 3.34 (dd, 1H), 3.23-3.15 (m, 2H), 2.76-2.69(m, 1H), 2.63 (s, 3H), 2.60-2.51 (m, 2H).

Synthesis of2-{[(2S)-1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-yl]amino}acetamide[82]

A mixture ofN-[(2S)-2-amino-3-phenylpropyl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine[6](100 mg, 0.28 mmol), 2-Bromoacetamide (38.5 mg, 0.28 mmol), andpotassium carbonate (77.5 mg, 0.56 mmol) in DMF (5 mL) was stirred atroom temperature for 3 days. A further portion of 2-Bromoacetamide (38.5mg, 0.28 mmol) was added and the reaction mixture stirred for a further24 h. The solvent was removed by rotary evaporation and the residuedissolved in methanol (2 mL), filtered then purified by preparative HPLC(method B). The appropriate fractions were combined, evaporated,triturated with diethyl ether and dried in the vac oven to give thetitle compound [82]: LCMS method: 1, RT:4.49 min, MI 414 [M+H]; ¹H NMR(1H, 300 MHz, d6-dmso) 9.16 (1H, s), 9.00 (1H, br m), 8.72-8.70 (2H, m),8.64-8.62 (1H, m), 8.23-8.21 (1H, m), 8.10-8.08 (2H, m), 7.32-7.26 (5H,m), 7.03 (1H, br s), 3.89-3.81 (1H, m), 3.53-3.45 (1H, m).

Synthesis ofN-(1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-yl)methanesulfonamide[83]

To a solution ofN-[(2S)-2-amino-3-phenylpropyl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine[6](100mg, 0.28 mmol) and DIPEA (98 mL, 0.56 mmol) in CH₂Cl₂ (10 mL) at roomtemperature was added methane sulfonyl chloride (22 mL, 0.28 mmol). Thereaction mixture was stirred at room temperature for 30 min, dilutedwith water and the organic phase separated, dried over MgSO₄ andpurified by column chromatography on silica, eluting with CH₂Cl₂containing 0-10% Methanol. The appropriate fractions were combined andconcentrated to give the title compound [83]: LCMS method: 1, RT: 4.04min, MI 435 [M+H]; ¹H NMR (1H, 300 MHz, d6-dmso) 9.18 (1H, s), 8.92 (1H,br t), 8.73-8.71 (2H, m), 8.65 (1H, d), 8.22-8.20 (2H, m), 8.16 (1H, d),7.39 (1H, br s), 7.33-7.31 (4H, m), 7.30-7.24 (1H, m), 3.93-3.88 (2H,m), 3.69-3.61 (1H, m), 2.99-2.92 (1H, m), 2.83-2.76 (1H, m), 2.35 (3H,s).

Synthesis of(1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-yl)urea[84]

A mixture ofN-[(2S)-2-amino-3-phenylpropyl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine[6](100 mg, 0.28 mmol), potassium cyanate (227 mg, 2.8 mmol), and aceticacid (4 mL) in water (4 mL) was stirred at 50° C. for 3 hours. A furtherportion of potassium cyanate (227 mg, 2.8 mmol) was added and thereaction mixture heated in a sealed tube in the microwave at 100° C. for30 min. The reaction mixture was concentrated under vacuum thenpartitioned between ethyl acetate and water. The target material wasfound to partially precipitate on the internal surface of the seperatingfunnel. This solid was collected and combined with the organic layerwhich was evaporated to dryness then dissolved in DMSO/Methanol (1 mL),the target material started to precipitate, water (2 mL) was added andthe solid was collected by filtration then dried in the vac oven to give(the title compound [84]: LCMS method: 1, RT:4.54 min, MI 398 [M+H]; ¹HNMR (1H, 300 MHz, d6-dmso) 9.18 (1H, s), 8.99 (1H, br t), 8.74-8.72 (2H,m), 8.64 (1H, d), 8.28-8.25 (2H, m), 8.12 (1H, d), 7.32-7.19 (5H, m),6.05 (1H, d), 5.48 (2H, s), 4.29-4.23 (1H, m), 3.88-3.80 (1H, m),3.69-3.60 (1H, m), 2.94-2.88 (1H, m), 2.83-2.76 (1H, m).

Synthesis of3-ethyl-1-(1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-yl)urea[85]

A solution ofN-[(2S)-2-amino-3-phenylpropyl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine[6](100 mg, 0.28 mmol) and ethyl isocyanate (19 mg, 0.27 mmol) in CH₂Cl₂(5 mL) was stirred at room temperature for 1 h. The reaction mixture wasconcentrated by rotary evaporation and the residue purified by columnchromatography on silica, eluting with CH₂Cl₂ containing 0-10% MeOH. Theappropriate fractions were combined, evaporated and the residuetriturated with diethyl ether then dried in the vacuum oven to give thetitle compound [85]. LCMS method: 1, RT:4.20 min, MI 428 [M+H]; ¹H NMR(1H, 300 MHz, d6-dmso) 9.17 (1H, s), 8.94 (1H, br t), 8.74-8.72 (2H, m),8.64 (1H, d), 8.28-8.24 (2H, m), 8.13 (1H, d), 7.32-7.20 (5H, m), 5.86(1H, d), 5.79 (1H, t), 4.29-4.22 (1H, m), 3.90-3.83 (1H, m), 3.70-3.61(1H, m), 2.94-2.77 (2H, m), 0.84 (3H, t).

Synthesis of(3aR)-5-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-1-one[86]

(R)-2-Benzyl-4-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A046]

To a solution of 2-Pyridin-4-yl-pyrido[2,3-d]pyrimidin-4-ol [A003](0.2g, 0.78 mmol) in DMA 93 mL), 2,4,6-Triisopropylbenzenesulfonyl chloride(0.26 g, 0.86 mmol), Et₃N (0.22 mL, 1.57 mmol) and DMAP (10 mg) wereadded successively. The mixture was stirred at rt for 2h and(R)-2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (0.2g, 0.94 mmol) was added. The reaction was stirred overnight and thesolvent was removed under reduced pressure. The product was purified byflash chromatography using 0 to 8% MeOH/DCM to give the title compound[A046](0.14 g, 39% yield). LCMS method: 1, RT:4.41 min, MI 453.27 [M+H].

(3aR)-5-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-1-one[86]

A solution of(R)-2-Hydroxymethyl-4-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A046](20 mg, 0.044 mmol) in CH₂Cl₂ was addeddrop-wise to a stirred solution of DAST (11 mL, 0.088 mmol) in CH₂Cl₂ (3mL) at 0° C. The reaction mixture was warmed to room temperature andstirred overnight. Aqueous NaHCO₃ was added the organic phase separated,loaded onto a SCX cartridge, washed with MeOH and eluted with ammonia inmethanol. The product was purified purified by preparative HPLC (methodA). The appropriate fractions were combined and concentrated to give thetitle compound [86]: LCMS method: 1, RT:2.95 min, MI 379 [M+H]; ¹H, NMR(1H, 300 MHz, CDCl₃): 9.03 (s, 1H), 8.60 (d, 2H), 8.29 (d, 2H), 8.24 (s,1H), 4.50 (m, 2H), 4.18 (d, 1H), 4.09 (m, 4H), 3.97 (dd, 1H), 3.31 (td,1H), 3.16 (td, 1H), 3.10 (dd, 1H).

Example [87] Synthesis of2-{4-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl}acetonitrile[87]

To a stirred mixture of1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine[31](90mg, 0.28 mmol) and NEt₃ (78 mL, 0.56 mmol) in DMA (2 mL) was addedChloroacetonitrile (26 mL, 0.42 mmol) and the mixture was stirred atroom temperature overnight. The crude reaction mixture was diluted withwater and extracted with CH₂Cl₂ (2×5 mL), the organic extracts werecombined washed with sat NaHCO₃ (2×10 mL) brine (10 mL) dried MgSO₄filtered and evaporated to give a brown oil which was purified by SXC-2ion exchange (1 g) to give the title compound [87] as a pale yellowsolid (0.085 g, 90% yield). LCMS method: 1, RT:4.90 min, MI 362 [M+H];¹H NMR (1H, 300 MHz, CDCl₃): 9.02 (1H, s), 8.97-8.77 (2H, m), 8.36-8.34(2H, m), 8.22 (s, 1H), 4.11 (3H, s), 3.81 (4H, br t), 3.65 (2H, s), 2.83(4H, br t).

General Synthesis of 2-Substituted-Piperazine Derivatives of GeneralFormula [F-008b] Scheme A2

2-substituted piperazine derivatives of general formula [F-008b] wereprepared by the reaction of(R)-1,1-Dioxo-tetrahydro-2-oxa-1λ⁶-thia-5,7a-diaza-indene-5-carboxylicacid tert-butyl ester [A049] with a phenol in the presence of a strongbase such as sodium hydride or potassium cyanide in a polar aproticsolvent such as DMF to give the 2-substituted piperazine derivatives ofgeneral formula [F-008a]. After reaction work up, typically by aliquid-liquid extraction or purification by acidic ion exchangecatch-release resin, followed by chromatographic purification. The N-Bocderivatives of general formula [F-008a] were deprotected under acidicconditions with a strong acid such as TFA, TCA, methanesulfonic acid,HCl or H₂SO₄ in a solvent such as DCM, DCE, THF, EtOH or MeOH and thecrude reaction product was purified by normal phase silica gelchromatography or reverse phase preparative HPLC to give the2-substituted-piperazine derivatives of general formula [F-008b].

Syntheisis of (R)-2-Phenoxymethyl-piperazine [A047]

(R)-1-Oxo-tetrahydro-2-oxa-1λ⁴-thia-5,7a-diaza-indene-5-carboxylic acidtert-butyl ester [A048]

A solution of (R)-3-Hydroxymethyl-piperazine-1-carboxylic acidtert-butyl ester (5.00 g, 23.118 mmol) in CH₂Cl₂ (330 mL) was preparedand cooled to 0° C. Imidazole (6.295 g, 92.472 mmol) and triethylamine(7.06 mL, 50.860 mmol) were added followed drop-wise addition of thionylchloride (1.94 mL, 26.586 mmol) as a solution in CH₂Cl₂ (20 mL) over 20min. The reaction mixture was allowed to warm to room temperature (icebath not removed) and the reaction mixture stirred at room temperaturefor 3 days. The reaction mixture was diluted with water (250 mL) and theorganic phase separated. The aqueous phase was extracted with CH₂Cl₂(3×50 mL) and the combined organic portions dried over MgSO₄, filteredand concentrated by rotary evaporation. The residue was purified bychromatography on silica, eluting with cyclohexane containing 0-50%EtOAc. The appropriate fractions were combined and concentrated to givethe title compound [A048](5.196 g, 86%) as a pale yellow oil thatsolidified on standing. ¹H NMR (1H, 400 MHz, d6-dmso) 4.81 (1H, dd),4.58 (1H, dd), 4.44 (1H, dd), 4.28 (1H, br d), 4.12 (1H, br d), 4.02(1H, br d), 3.93-3.87 (2H, m), 3.67-3.56 (2H, m), 3.46-3.34 (2H, m),3.14-3.06 (1H, d), 3.01-2.69 (4H, br m), 2.55 (1H, dt), 1.42 (s, 9H),1.41 (s, 9H).

(R)-1,1-Dioxo-tetrahydro-2-oxa-1⁶-thia-5,7a-diaza-indene-5-carboxylicacid tert-butyl ester [A049]

A stirred solution of(R)-1-Oxo-tetrahydro-2-oxa-1λ⁴-thia-5,7a-diaza-indene-5-carboxylic acidtert-butyl ester [A048](2.99 g, 11.409 mmol) in anhydrous MeCN (25 mL)was prepared under nitrogen and cooled to 0° C. Sodium (meta)periodate(2.464 g, 11.523 mmol) was added followed by ruthenium (III) chloridehydrate (24 mg, 0.114 mmol) (reaction mixture turns brown) and water (25mL). The reaction mixture was stirred at 0° C. for 10 min and thenremoved from ice bath and stirred at room temperature for 10 min. TLCshows complete conversion to a new, slightly more polar spot. Thereaction mixture was diluted with sat. NaHCO₃ (aq) (100 mL) andextracted with CH₂Cl₂ (3×40 mL). The combined organic extracts weredried and concentrated by rotary evapoartion. The residue was purifiedby chromatography on silica, eluting with cyclohexane containing 0-50%EtOAc to give the title compound [A049](1.72 g, 54%) as a pale yellowsolid. ¹H NMR (1H, 500 MHz, CDCl₃) 4.63 (1H, dd), 4.25-4.07 (3H,overlapping t and broad m), 3.67-3.61 (1H, m), 3.45 (1H, br. d, J=11.2Hz), 3.13 (1H, br. s), 2.98-2.94 (2H, br. m), 1.47 (9H, s).

(R)-3-Phenoxymethyl-piperazine-1-carboxylic acid tert-butyl ester [A050]

A solution of(R)-1,1-Dioxo-tetrahydro-2-oxa-126-thia-5,7a-diaza-indene-5-carboxylicacid tert-butyl ester [A049](200 mg, 0.719 mmol) in anhydrous DMF (5 mL)was prepared under nitrogen. Sodium phenolate (88 mg, 0.754 mmol) wasadded and the reaction mixture heated to 50° C. overnight. A further0.25 equivalents of sodium phenolate was added and heating continued fora further 5 hours. The reaction mixture was cooled to room temperatureand 2 mL of 2M HCl (aq) was added. The mixture was stirred at roomtemperature for 1 hour. The reaction mixture was loaded onto a 10 g SCXcartridge, washing with methanol and eluting with 7N ammonia in MeOH.The ammonia fractions were combined and concentrated under reducedpressure. The residue was purified by chromatography on silica, elutingwith CH₂Cl₂ containing 0-10% MeOH. The appropriate fractions werecombined and concentrated to give the title compound [A00?](75 mg, 36%)as a colourless oil. LCMS method: 1, RT:2.85 min, MI 293 [M+H]; ¹H NMR(1H, 500 MHz, CDCl₃) 7.31-7.24 (2H, m), 6.97 (1H, t), 6.91 (2H, d), 4.05(1H, br s), 3.97-3.95 (2H, m), 3.88-3.85 (1H, m), 3.09 (1H, br s),3.04-3.01 (1H, br m), 2.96-2.91 (1H, br m), 2.83-2.74 (1H, br m), 2.74(1H, br s), 2.14 (1H, br s)1.48 (9H, s).

(R)-2-Phenoxymethyl-piperazine [A047]

A solution of (R)-3-Phenoxymethyl-piperazine-1-carboxylic acidtert-butyl ester [A050](98 mg, 0.332 mmol) in anhydrous dioxane (1 mL)was prepared and 4M HCl in dioxane (5 mL) was added. The reactionmixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated by rotary evaporation to give a pale pinksolid. The product was dissolved in MeOH and loaded onto a SCXcartridge, washing with MeOH and eluting with 7N ammonia in MeOH. Theammonia fraction was concentrated by rotary evaporation to give thetitle compound [A047](58 mg, 91%) as a pale oil that crystalised onstanding. LCMS method: 1, RT:0.56 min, MI 193 [M+H]; ¹H NMR (1H, 500MHz, CDCl₃) 7.30-7.27 (2H, m), 6.97-6.94 (1H, m), 6.91-6.90 (2H, m),3.92-3.90 (1H, m), 3.83-3.83 (1H, m), 3.17-3.12 (1H, m), 3.07-3.03 (2H,m), 2.99-2.96 (1H, m), 2.92-2.87 (1H, m), 2.84-2.79 (1H, m) 2.63 (1H,dd).

Synthesis of (R)-2-(2-Fluoro-phenoxymethyl)-piperazine [A051]

(R)-3-(2-Fluoro-phenoxymethyl)-piperazine-1-carboxylic acid tert-butylester [A052]

A suspension of sodium hydride (69 mg, 1.726 mmol) in anhydrous DMF (5mL) was prepared and 2-fluorophenol (0.15 mL, 1.726 mmol) addeddropwise. The reaction mixture was stirred at room temperature for 10min then(R)-1,1-Dioxo-tetrahydro-2-oxa-1⁶-thia-5,7a-diaza-indene-5-carboxylicacid tert-butyl ester [A051](400 mg, 1.438 mmol) was added. The reactionmixture was heated to 50° C. overnight. The reaction mixture was cooledto room temperature and 2M HCl (aq) (1.4 mL, 2.875 mmol) was added. Thereaction mixture was stirred at room temperature for 1.5 h. The reactionmixture was loaded onto a SCX cartridge, washing with methanol andeluting with 7N ammonia in MeOH. The ammonia fractions were combined andconcentrated by rotary evaporation. The residue was purified bychromatography on silica, eluting with CH₂Cl₂ containing 0-10% MeOH. Theappropriate fractions were combined and concentrated to give the titlecompound [A052](318 mg, 71%) as a colourless oil. LCMS method: 1,RT:2.92 min, MI 311 [M+H]; ¹H NMR (1H, 500 MHz, CDCl₃) 7.10-7.04 (2H,m), 6.99-6.91 (2H, m), 4.04-3.89 (4H, m and overlapping br s), 3.14-3.11(1H, m), 3.03 (1H, br d), 2.96 (1H, br t), 2.83-2.79 (1H, m), 2.75 (1H,br s), 2.23 (1H, br s), 1.48 (9H, s).

(R)-2-(2-Fluoro-phenoxymethyl)-piperazine [A051]

Following the procedure described in scheme A2,(R)-3-(2-Fluoro-phenoxymethyl)-piperazine-1-carboxylic acid tert-butylester [A052](310 mg, 1.00 mmol) was treated with 4M HCl in dioxane (2mL) to give the title compound [A051](196 mg, 93%) as a pale yellow oil.LCMS method: 1, RT:0.75 min, MI 211 [M+H];LCMS method 1LCMS5, RT: 0.75min, MI: 211 [M+1]. ¹H NMR (1H, 500 MHz, CDCl₃) 7.10-7.03 (2H, m),6.98-6.89 (2H, m), 4.00-3.97 (1H, m), 3.91-3.88 (1H, m), 3.23-3.18 (1H,m), 3.08-3.03 (2H, m), 3.00-2.98 (1H, m), 2.94-2.89 (1H, m), 2.85-2.80(1H, m), 2.66-2.61 (1H, m).

Synthesis of (R)-2-(4-Fluoro-phenoxymethyl)-piperazine [A053]

(R)-3-(4-Fluoro-phenoxymethyl)-piperazine-1-carboxylic acid tert-butylester [A054]

Following the procedure described in Scheme A2 step 1,(R)-1,1-Dioxo-tetrahydro-2-oxa-1λ⁶-thia-5,7a-diaza-indene-5-carboxylicacid tert-butyl ester [A048](400 mg, 1.43 8 mmol) was reacted with4-fluorophenol (193 mg, 1.726 mmol) to give the title compound[A054](100 mg, 22%) as a colourless oil. LCMS method: 1, RT:3.00 min, MI311 [M+H]. ¹H NMR (1H, 500 MHz, CDCl₃) 6.99-6.96 (2H, m), 6.85-6.83 (2H,m), 4.06 (1H, br s), 3.95 (1H, br s), 3.95-3.90 (1H, m), 3.84-3.80 (1H,m), 3.10-3.05 (1H, m), 3.03 (1H, br d), 2.93 (1H, br t), 2.83-2.78 (1H,m), 2.72 (1H, br s), 2.10 (1H, br s), 1.48 (9H, s).

(R)-2-(4-Fluoro-phenoxymethyl)-piperazine [A053]

Following the procedure described in example Scheme A2, step 4,(R)-3-(4-Fluoro-phenoxymethyl)-piperazine-1-carboxylic acid tert-butylester [A054](100 mg, 0.322 mmol) was treated with 4M HCl in dioxane (2mL) to give the title compound [A053](68 mg, 100%) as a colourless oilthat solidified on standing. LCMS method: 1, RT:0.59 min, MI 211 [M+H];¹H NMR (1H, 500 MHz, CDCl₃) 6.99-6.95 (2H, m), 6.85-6.82 (2H, m),3.88-3.86 (1H, m), 3.81-3.78 (1H, m), 3.15-3.10 (1H, m), 3.05-3.02 (2H,m), 2.98-2.96 (1H, m), 2.91-2.86 (1H, m), 2.83-2.78 (1H, m), 2.63-2.58(1H, m).

Synthesis of (S)-Piperazin-2-yl-acetonitrile [A055]

(S)-3-Cyanomethyl-piperazine-1-carboxylic acid tert-butyl ester [A056]

Following the procedure described in Scheme A1, step 3,(R)-1,1-Dioxo-tetrahydro-2-oxa-12⁶⁻thia-5,7a-diaza-indene-5-carboxylicacid tert-butyl ester [A048](1.52 g, 5.46 mmol) was reacted with KCN(356 mg, 5.46 mmol) to give the title compound [A056](850 mg, 69%). ¹HNMR (1H, 500 MHz, CDCl₃) 3.95 (1H, br s), 3.84 (1H, br d), 3.03-2.92(3H, m), 2.82-2.75 (1H, m), 2.70 (1H, br s), 2.51-2.41 (2H, m), 1.49(9H, s). LCMS method: 1, RT:1.39 min, MI 226 [M+H].

(S)-Piperazin-2-yl-acetonitrile [A055]

Following the procedure described in example Scheme A2, step 4,(S)-3-Cyanomethyl-piperazine-1-carboxylic acid tert-butyl ester[A056](800 mg, 3.55 mmol) was treated with 4M HCl in dioxane to give thetitle compound [A055](434 mg, 98%) as a pale orange solid. LCMS method:1, RT:0.49 min, MI 126 [M+H]; ¹H NMR (1H, 500 MHz, CDCl₃) 3.06-2.99 (3H,m), 2.93-2.90 (1H, m), 2.87-2.82 (1H, m), 2.77-2.72 (1H, m), 2.56-2.51(1H, m), 2.44-2.42 (2H, m).

Synthesis of Phenyl-(S)-piperidin-3-yl-amine [A057]

(S)-3-Phenylamino-piperidine-1-carboxylic acid tert-butyl ester [A058]

A solution of (S)-3-Amino-piperidine-1-carboxylic acid tert-butyl ester(500 mg, 2.497 mmol), Pd2(dba)3 (95 mg, 0.104 mmol) and2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (61 mg, 0.156mmol) in toluene (5 mL) was prepared under nitrogen. The solvent wasdegasses and sodium tert-butoxide (280 mg, 2.912 mmol) was addedfollowed by bromobenzene (0.22 mL, 2.080 mmol). The reaction mixture washeated to 100° C. for 24 h. The reaction mixture was cooled to roomtemperature and concentrated by rotary evaporation. The residue wasfiltered through a plug of silica, eluting with CH₂Cl₂. The eluent wasconcentrated by rotary evaporation. The crude residue was purified bychromatography on silica, eluting with cyclohexane containing 5-50%EtOAc. The appropriate fractions were combined and concentrated to givethe title compound [A058](535 mg, 78%) as a pale yellow oil thatsolidified on standing. LCMS method: 1, RT:5.51 min, MI 227 [M+H]; ¹HNMR (1H, 500 MHz, CDCl₃) 7.20-7.17 (2H, m), 6.71 (1H, t), 6.64 (2H, d),4.02 (1H, br s), 3.74-3.70 (1H, m), 3.63 (1H, br s), 3.39 (1H, br m),3.09 (1H, br m), 2.89 (1H, br s), 2.02-1.99 (1H, m), 1.78-1.73 (1H, m),1.59-1.51 (2H, m), 1.46 (9H, s).

Phenyl-(S)-piperidin-3-yl-amine [A057]

Following the procedure described in Scheme A2, step 4,(S)-3-phenylamino-piperidine-1-carboxylic acid tert-butyl ester[A058](138 mg, 0.5 mmol) was treated with 4 HCl in dioxane (2 mL) togive the title compound [A057](85 mg, 97%) as a pale yellow oil. LCMSmethod: 1, RT:0.96 min, MI 177 [M+H].

General Synthesis of8-Substituted-1-Yl-2-Pyridin-4-Yl-Pyrido[3,4-d]Pyrimidine Derivatives ofGeneral Formula [F-011] Scheme A3

4-Substituted 8-Chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin derivativesof general formula [F-010] were prepared by the reaction of a8-Chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivative ofgeneral formula [F-009] with 2,4,6-triisopropylbenzenesulfonyl chloridein a polar aprotic solvent such as DMA, DMF, NMP with a tertiaryalkylamine base such as Et₃N, DIPEA or NMM and a catalytic amount ofDMAP. The intermediate6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-8-Chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidini-4-yl ester wasthen reacted with a primary or secondary amino derivative, of generalformula [F-003], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, the thecrude reaction product was purified by normal phase chromatography orreverse phase preparative HPLC. The 4-Substituted8-Chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin derivatives of generalformula [F-010] were reacted in a Suzuki type reaction utilising asuitable boronic acid or boronic ester, of general formula [F-012], apalladium catalyst such as Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂a base such as Et₃N,KOH, Na₂CO₃ or NaOH in a polar solvent such as EtOH, THF, DMA or dioxaneat high temperature either by heating thermally or using a microwavereactor. After reaction work up, typically by a liquid-liquid extractionor purification by acidic ion exchange catch-release, the N-Bocderivatives were deprotected under acidic conditions with a strong acidsuch as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in a solvent suchas DCM, DCE, THF, EtOH or MeOH and the crude reaction product waspurified by normal phase chromatography or reverse phase preparativeHPLC.

Synthesis ofN-{3-[4-((S)-2-Amino-3-phenyl-propylamino)-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-8-yl]-phenyl}-methanesulfonamide[88]

[(S)-1-Benzyl-2-(8-chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [A059]

To a solution of 2-Pyridin-4-yl-pyrido[2,3-d]pyrimidin-4-ol [A005](1 g,3.8 mmol) in DMA (15 mL), 2,4,6-Triisopropylbenzenesulfonyl chloride(1.3 g, 4.25 mmol), Et₃N (1.1 mL, 7.73 mmol) and DMAP (0.1 g) were addedsuccessively. The mixture was stirred at rt for 1 h then((S)-2-Amino-1-benzyl-ethyl)-carbamic acid tert-butyl ester (1.16 g,4.64 mmol) was added. The reaction was stirred overnight and the solventwas removed under reduced pressure and the crude mixture was purified byflash chromatography (SP1 [eluent: DCM/MeOH: 1/0 then 95/5 then 9/1]) togive the title compound: LCMS method: 1, RT:5.76 min, MI 492 [M+H]

N-{3-[4-((S)-2-Amino-3-phenyl-propylamino)-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-8-yl]-phenyl}-methanesulfonamide[88]

A microwave vial was charged with[(S)-1-Benzyl-2-(8-chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [A059](0.07 g, 0.142 mmol),3-(methanesulfonylamino)phenylboronic acid pinacol ester (0.06 g, 0.2mmol), Pd(Ph3P)₄ (0.017 g, 0.014 mmol), aq K3PO4 (0.5M, 0.57 mL, 0.28mmol) and DMA (1 mL). The vial was heated under microwave irradiations(150° C., 10 min). The solvent was removed under reduced pressure. Thecrude was purified by Column chromatography (Eluent: DCM/MeOH: 1:0 to9/1). The purified compound was solubilised in DCM (2 mL) and TFA (0.5mL) was added. The solution was stirred 3h and then was poured onto SCX2column, washed with MeOH and the expected product was released using asolution MeOH/NH3 2M which was used without further purification to givethe title compound [88]: LCMS method: 1, RT:3.01 min, MI 526 [M+H]; NMR1H (1H, 300 MHz, d6-dmso) 8.70 (d, 2H), 8.68 (d, 1H), 8.25 (d, 2H), 8.14(d, 1H), 8.04 (d, 2H), 7.37-7.24 (m, 7H), 3.91-3.86 (m, 1H), 3.46-3.33(m, 2H), 3.10 (s, 3H), 2.77-2.69 (m, 2H).

The following compounds were synthesised according to the generalsynthesis shown in scheme [A3]:

Ex SM Boronic acid Analysis Name 89 [A059]

Method 1: RT: 3.01 min, MI: 423 [M + H] (1H, 300 MHz, d6-dmso) 8.76 ppm(2H, dd), 8.67 ppm (1H, d), 8.29 ppm (1H, s), 8.15 ppm (1H, d), 8.08 ppm(2H, dd), 7.71 ppm (1H, d), 7.61 ppm (1H, d), 7.41-7.30 ppm (5H, m),3.97 ppm, (1H, d), 3.58 ppm (2H, br s), 3.35 ppm (2H, m), 2.97- 2.80 ppm(2H, m) N-[(2S)-2-amino-3- phenylpropyl]-8- (1H-pyrazol-5-yl)-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- amine 90 [A059]

Method 1: RT: 3.62 min, MI: 433 [M + H] (1H, 300 MHz, d6-dmso) 9.47 ppm(1H, br s), 8.70 ppm (1H, d), 8.67 ppm (2H, dd), 8.42 ppm (1H, br s),8.18-8.14 ppm (3H, m), 7.90 ppm (2H, dd), 7.57-7.46 ppm (3H, m),7.42-7.31 ppm (5H, m), 3.99 ppm (1H, d), 3.67-3.51 ppm (2H, m), 3.01 ppm(1H, dd), 2.83 ppm (1H, dd) N-[(2S)-2-amino-3- phenylpropyl]-8-phenyl-2-(pyridin- 4-yl)pyrido[3,4- d]pyrimidin-4- amine 91 [A059]

Method 1: RT: 2.93 min, MI: 449 [M + H] (1H, 300 MHz, d6-dmso),8.85-8.85 ppm (1H, br s), 8.70 ppm (2H, d), 8.62 ppm (1H, d), 8.12 ppm(2H, d), 8.04 ppm (1H, d), 8.00 ppm (2H, d), 7.39- 7.27 ppm (5H, m),6.91 ppm (2H, d), 3.97-3.86 ppm (1H, m), 3.54- 3.44 ppm (2H, m), 2.83ppm (2H, br s) 4-(4-{[(2S)-2- amino-3- phenylpropyl]- amino}-2-(pyridin-4-yl)pyrido[3,4- d]pyrimidin-8- yl)phenol 92 [A059]

Method 1: RT: 3.00 min, MI: 449 [M + H] (1H, 300 MHz, d6-dmso),8.73-8.69 ppm (3H, t), 8.16 ppm (1H, d), 8.04 ppm (2H, d), 7.64- 7.62ppm (2H, m), 7.36-7.23 ppm (5H, m), 6.88 ppm (1H, dd), 3.88 ppm (1H, d),3.46-3.30 ppm (2H, m), 2.77-2.74 ppm (2H, m) 3-(4-{[(2S)-2- amino-3-phenylpropyl]- amino}-2-(pyridin- 4-yl)pyrido[3,4- d]pyrimidin-8-yl)phenol 93 [A059]

Method 1: RT: 3.16 min, MI: 463 [M + H] (1H, 300 MHz, d6-dmso),8.65-8.63 ppm (3H, t), 8.19 ppm (1H, d), 7.87 ppm (2H, d), 7.48 ppm (1H,dt), 7.36-7.24 ppm (5H, m), 7.17 ppm (1H, d), 7.07 ppm (1H, t),3.92-3.84 ppm (1H, dd), 3.61 ppm (3H, s), 3.44- 3.29 ppm (2H, m),2.77-2.75 ppm (2H, m) N-[(2S)-2-amino-3- phenylpropyl]-8-(2-methoxyphenyl)-2- (pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- amine 94[A059]

Method 1: RT: 3.54 min, MI: 463 [M + H] (1H, 300 MHz, d6-dmso), 8.70 ppm(3H, d), 8.18 ppm (1H, d), 8.02 ppm (2H, d), 7.80- 7.76 ppm (2H, m),7.45 ppm (1H, t), 7.34-7.24 ppm (5H, m), 7.07 ppm (1H, dd), 3.88 ppm(1H, d), 3.83 ppm (3H, s), 3.43- 3.33 ppm (2H, m), 2.77-2.73 ppm (2H, m)N-[(2S)-2-amino-3- phenylpropyl]-8-(3- methoxyphenyl)-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- amine 95 [A059]

Method 1: RT: 3.56 min, MI: 463 [M + H] (1H, 300 MHz, d6-dmso), 8.70 ppm(2H, d), 8.65 ppm (1H, d), 8.24 (2H, d), 8.10 ppm (1H, d), 8.04 ppm (2H,d), 7.36-7.23 ppm (5H, m), 7.09 ppm (2H, d), 3.89- 3.84 ppm (1H, m),3.85 ppm (3H, s), 3.44-3.30 ppm (2H, m), 2.74 ppm (2H, t)N-[(2S)-2-amino-3- phenylpropyl]-8-(4- methoxyphenyl)-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- amine 96 [A059]

Method 1: RT: 3.46 min, MI: 467 [M + H] (1H, 300 MHz, d6-dmso) 8.69 ppm(2H, d), 8.63 ppm (2H, dd), 8.28 ppm (1H, d), 8.19- 8.16 ppm (1H, m),8.01 ppm (1H, d), 7.84 ppm (2H, dd), 7.64- 7.60 ppm (1H, m), 7.36-7.23ppm (5H, m), 3.92-3.84 ppm (1H, m), 3.44-3.25 ppm (2H, m), 2.76- 2.74ppm (2H, m) N-[(2S)-2-amino-3- phenylpropyl]-8-(2- chlorophenyl)-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- amine 97 [A059]

Method 1: RT: 3.69 min, MI: 473 [M + H] (1H, 300 MHz, d6-dmso): 8.68 (d,3H), 8.48 (d, 1H), 8.18- 8.15 (m, 2H), 8.06 (d. 1H), 8.01 (d, 1H), 7.73(d, 1H), 7.36-7.26 (m, 5H), 7.10 (d, 1H), 3.88 (d, 1H), 3.45-3.37 (m,2H), 2.77-2.73 (m, 2H). N-[(2S)-2-amino-3- phenylpropyl]-8-(1-benzofuran-5-yl)-2- (pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- amine 98[A059]

Method 1: RT: 2.98 min, MI: 437 [M + H] (1H, 300 MHz, d6-dmso) 8.77 (s,1H), 8.75 (d, 2H), 8.54 (d, 1H), 8.44 (s, 1H), 8.12 (d, 2H), 7.97 (d,1H), 7.36-7.27 (m, 5H), 3.99 (s, 3H), 3.87 (d, 1H), 3.43-3.35 (m, 2H),2.77-2.74 (m, 2H). N-[(2S)-2-amino-3- phenylpropyl]-8-(1-methyl-1H-pyrazol- 4-yl)-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-amine 99 [A059]

Method 1: RT: 2.58 min, MI: 434 [M + H] (1H, 300 MHz, d6-dmso): 9.33 (d,1H), 8.73-8.66 (m, 3H), 8.51 (td, 1H), 8.21 (d, 1H), 7.98 (d, 2H), 7.57(dd, 1H), 7.37-7.27 (m, 5H), 3.92-3.84 (m, 1H), 3.47- 3.38 (m, 2H),2.78-2.76 (m, 2H). N-[(2S)-2-amino-3- phenylpropyl]-8- (pyridin-3-yl)-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- amine 100 [A059]

Method 1: RT: 2.41 min, MI: 434 [M + H] (1H, 300 MHz, d6-dmso):8.77-2.75 (m, 3H), 8.71 (d, 2H), 8.28 (d, 1H), 8.15 (d, 2H), 8.02 (d,2H), 7.36-7.26 (m, 5H), 3.91- 3.86 (m, 1H), 3.46-3.36 (m, 2H), 2.78-2.73(m, 2H). N-[(2S)-2-amino-3- phenylpropyl]-2,8- bis(pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- amine 101 [A059]

Method 1: RT: 3.90 min, MI: 479 [M + H] (1H, 300 MHz, d6-dmso):8.75-8.73 (m, 3H), 8.54 (d, 1H), 8.49 (s, 1H), 8.11 (d, 2H), 7.98 (d,1H), 7.35-7.25 (m, 5H), 4.07 (d, 2H), 3.88-3.84 (m, 1H), 3.43- 3.36 (m,2H), 2.74-2.70 (m, 2H), 2.23-2.14 (m, 1H), 0.91 (d, 6H).N-[(2S)-2-amino-3- phenylpropyl]-8-[1- (2-methylpropyl)-1H-pyrazol-4-yl]-2- (pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- amine 102[A059]

Method 1: RT: 4.05 min, MI: 466 [M + H] N-[(2S)-2-amino-3-phenylpropyl]-8-(3- chlorophenyl)-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- amine 103 [A059]

Method 1: RT: 4.08 min, MI: 467 [M + H] (1H, 300 MHz, d6-dmso) 8.72-8.62(m, 3H), 8.35 (s, 1H), 8.23 (d, 2H), 8.19 (d, 1H), 7.94 (d, 2H), 7.62(d, 2H), 7.39-7.32 (m, 5H), 4.02-3.94 (m, 1H), 3.59- 3.50 (m, 2H),3.00-2.92 (m, 1H), 2.85-2.80 (m, 1H). N-[(2S)-2-amino-3-phenylpropyl]-8-(4- chlorophenyl)-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- amine 104 [A059]

Method 1: RT: 2.72 min, MI: 437 [M + H] (1H, 300 MHz, d6-dmso): 8.72 (d,2H), 8.72 (d, 1H), 8.22 (d, 1H), 8.04 (d, 2H), 7.61 (d, 1H), 7.35-7.23(m, 5H), 7.09 (d, 1H), 4.02 (s, 3H), 3.90-3.85 (m, 1H), 3.44-3.33 (m,2H), 2.75-2.71 (m, 2H). N-[(2S)-2-amino-3- phenylpropyl]-8-(1-methyl-1H-pyrazol- 5-yl)-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-amine 105 [A059]

(1H, 300 MHz, d6-dmso): 8.68-8.74 (m, 3H), 8.38 (d, 1H), 8.35 (s, 1H),8.22 (d, 1H), 7.96 (d, 2H), 7.32-7.40 (m, 6H), 6.98- 7.04 (m, 2H), 3.98(d, 1H), 3.50- 3.58 (m, 2H), 2.95 (dd, 1H), 2.85 (dd, 1H).2-(4-{[(2S)-2- amino-3- phenylpropyl]amino}- 2-(pyridin-4-yl)pyrido[3,4- d]pyrimidin-8- yl)phenol 106 [A059]

Method 1: RT: 4.74 min, MI: 543 [M + H] (1H, 300 MHz, d6-dmso): 8.75 (d,1H), 8.66 (d, 2H), 8.52 (s, 1H), 8.26-8.18 (m, 2H), 7.99 (d, 2H), 7.83(d, 1H), 7.80 (s, 1H), 7.72 (d, 1H), 7.67 (t, 1H), 7.52 (t, 1H), 7.46(d, 1H), 7.38- 7.30 (m, 5H), 4.00-3.92 (m, 1H), 3.58-3.52 (m, 2H),2.91-2.86 (m, 2H). N-[(2S)-2-amino-3- phenylpropyl]-8-[3-(3-chlorophenyl)- phenyl]-2-(pyridin- 4-yl)pyrido[3,4- d]pyrimidin-4-amine 107 [A059] Method (1H, 300 MHz, d6-dmso): N-[(2S)-2-amino-3- 1:RT: 8.74 (d, 1H), 8.70 (d, 2H), 8.34 phenylpropyl]-8-[4- 4.73 )d, 2H),8.27 (d, 2H), 8.18 (d, (4-chlorophenyl)- min, 1H), 8.01 (d, 2H), 7.88(d, 2H), phenyl]-2-(pyridin- MI: 543 7.83 (d, 2H), 7.57 (d, 2H), 7.40-4-yl)pyrido[3,4- [M + H] 7.31 (m, 5H), 3.99-3.93 (m, 1H), d]pyrimidin-4-3.60-3.53 (m, 2H), 2.89-2.82 (m, amine 2H). 108 [A059]

Method 1: RT: 2.83 min, MI: 435 [M + H] (1H, 300 MHz, d6-dmso): 9.50 (s,2H), 9.27 (s, 1H), 8.71 (d, 1H), 8.69 (d, 2H), 8.22 (d, 1H), 7.93 (d,2H), 7.37-7.28 (m, 5H), 3.92-3.85 (m, 1H), 3.47-3.38 (m, 2H), 2.79-2.76(m, 2H). N-[(2S)-2-amino-3- phenylpropyl]-2- (pyridin-4-yl)-8-(pyrimidin-5- yl)pyrido[3,4- d]pyrimidin-4- amine 109 [A059]

Method 1: RT: 2.43 min, MI: 448 [M + H] (1H, 300 MHz, d6-dmso): 8.69 (d,2H), 8.65 (d, 1H), 8.13 (d, 1H), 8.04 (d, 2H), 7.38-7.26 (m, 7H), 7.17(t, 1H), 6.68 (d, 1H), 5.16 (brs, 2H), 3.91-3.85 (m, 1H), 3.45-3.35 (m,2H), 2.77-2.75 (m, 2H). N-[(2S)-2-amino-3- phenylpropyl]-8-(3-aminophenyl)-2- (pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- amine 110[A059]

Method 1: RT: 4.07 min, MI: 473 [M + H] (1H, 300 MHz, d6-dmso): 8.78 (d,2H), 8.72 (d, 1H), 8.53 (s, 1H), 8.16 (d, 3H), 7.90 (d, 1H), 7.71 (d,1H), 7.43 (t, 1H), 7.36-7.26 (m, 6H), 3.92-3.84 (m, 1H), 3.52-3.45 (m,2H), 2.83-2.79 (m, 2H). N-[(2S)-2-amino-3- phenylpropyl]-8-(1-benzofuran-7-yl)-2- (pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- amine 111[A059]

Method 1: RT: 1.81 min, MI: 453 [M + H] (1H, d6-DMSO, 500 MHz) 8.67 (d,2H), 8.30-8.16 (m, 1H), 8.01 (d, 2H), 7.36-7.24 (m, 7H), 6.82 (d, 1H),3.86-3.73 (m, 1H), 2.75- 2.72 (m, 2H). N-[(2S)-2-amino-3-phenylpropyl]-8-(5- methylthiophen-2- yl)-2-(pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- amine 112 [A059]

Method 1: RT: 3.02 min, MI: 452 [M + H] N-[(2S)-2-amino-3-phenylpropyl]-8- (dimethyl-1,2- oxazol-4-yl)-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- amine 113 [A059]

Method 1: RT: 3.42 min, MI: 426 [M + H] C (1H, 300 MHz, d6-dmso): 8.99(d, 1H), 8.71 (d, 2H), 8.58 (d, 1H), 8.44 (s, 1H), 8.03 (d, 1H), 7.96(d, 2H), 7.82 (t, 1H), 7.39-7.29 (m, 5H), 4.00-3.94 (m, 1H), 3.68-3.48(m, 2H), 303 (dd, 1H), 2.84 (dd, 1H). N-[(2S)-2-amino-3-phenylpropyl]-8- (furan-3-yl)-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- amine 114 [A059]

Method 1: RT: 3.55 min, MI: 439 [M + H] (1H, 300 MHz, d6-dmso): 8.96 (d,1H), 8.74 (d, 2H), 8.63 (d, 1H), 8.13-8.09 (m, 4H), 7.64 (d, (dd, 1H),7.36-7.25 (m, 5H), 3.92- 3.85 (m, 1H), 3.45-3.36 (m, 2H), 2.76-2.71 (m,2H). N-[(2S)-2-amino-3- phenylpropyl]-2- (pyridin-4-yl)-8- (thiophen-3-yl)pyrido[3,4- d]pyrimidin-4- amine 115 [A059]

Method 1: RT: 3.26 min, MI: 423 [M + H] (1H, 300 MHz, d6-dmso): 8.76 (d,2H), 8.61 (d, 1H), 8.12- 8.06 (m, 3H), 7.95 (s, 1H), 7.36- 7.26 (m, 5H),6.80-6.78 (m, 1H), 3.92-3.85 (m, 1H), 3.46-3.39 (m, 2H), 2.78-2.75 (m,2H). N-[(2S)-2-amino-3- phenylpropyl]-8- (furan-2-yl)-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- amine 116 [A059]

Method 1: RT: 2.23 min, MI: 473 [M + H] N-[(2S)-2-amino-3-phenylpropyl]-8- (1H-1,3- benzodiazol-5-yl)- 2-(pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- amine 117 [A059]

Method 1: RT: 3.72 min, MI: 477 [M + H] N-[(2S)-2-amino-3-phenylpropyl]-8-(3- ethoxyphenyl)-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- amine 118 [A059]

N-[(2S)-2-amino-3- phenylpropyl]-8-(2- methylphenyl)-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4- amine 119 [A059]

N-[(2S)-2-amino-3- phenylpropyl]-8-(3- methylphenyl)-2- (pyridin-4-yl)pyrirido[3,4- d]pyrimidin-4- amine 120 [A059]

Method 1: RT: 3.55 min, MI: 499 [M + H] (1H, 300 MHz, d6-dmso): 8.87(brs, 1H), 8.70 (d, 1H), 8.67 (d, 2H), 8.18 (d, 1H), 8.14- 8.09 (m, 3H),7.91 (d, 1H), 7.77 (brs, 1H), 7.56 (t, 1H), 7.36-7.26 (m, 5H), 6.74 (d,1H), 3.94-3.85 (m, 1H), 3.44-3.39 (m, 2H), 2.77- 2.74 (m, 2H).N-[(2S)-2-amino-3- phenylpropyl]-8-[3- (1H-pyrazol-5- yl)phenyl]-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- amine 121 [A059]

N-[(2S)-2-amino-3- phenylpropyl]-8-[5- (aminomethyl)- furan-2-yl]-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- amine

General synthesis of8-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofGeneral Formula [FO11] Scheme A4

8-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F011] were prepared by reaction of a 4-Substituted8-Chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin derivatives of generalformula [F-010] in a Stille type reaction utilising a suitable stannaneof general formula [F013], a palladium catalyst such as Pd(PPh₃)₄ orPd(PPh₃)₂Cl₂ a base such as K₃PO₄, in a polar solvent such as DMA ordioxane at high temperature either by heating thermally or using amicrowave reactor. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, theN-Boc derivatives were deprotected under acidic conditions with a strongacid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in a solventsuch as DCM, DCE, THF, EtOH or MeOH and the crude reaction product waspurified by normal phase chromatography or reverse phase preparativeHPLC.

Synthesis of(R)-3-Phenyl-N¹-(2-pyridin-4-yl-8-pyridin-2-yl-pyrido[3,4-d]pyrimidin-4-yl)-propane-1,2-diamine[122]

(R)-3-Phenyl-N¹-(2-pyridin-4-yl-8-pyridin-2-yl-pyrido[3,4-d]pyrimidin-4-yl)-propane-1,2-diamine[122]

A microwave vial was charged with[(S)-1-Benzyl-2-(8-chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [A059](0.07 g, 0.142 mmol),2-(Tributylstannyl)pyridine (0.068 g, 0.185 mmol), Pd(Ph₃P)₄ (0.016 g,0.014 mmol), LiCl (0.018 g, 0.428 mmol) and DMA (1.5 mL). The mixturewas heated under microwave irradiation (150° C., 10 min) and the solventwas removed under reduced pressure. The crude was purified by Columnchromatography (Eluent: DCM/MeOH: 1:0 to 9:1). The purified compound wassolubilised in DCM and 0.5 mL of TFA was added. The solution was stirred3h and then was poured on a SCX column, washed with MeOH and theexpected product was released using a solution MeOH/NH3 2M, the basicsolvent was concentrated under reduced pressure to yield the titlecompound as a yellow solid which was was used without furtherpurification: LCMS method: 1, RT:2.34 min, MI 434 [M+H]; ¹H NMR (1H, 500MHz, CDCl₃); 8.70-8.76 (m, 2H), 8.63 (d, 2H), 8.42 (brs, 1H), 8.27 (d,1H), 7.96 (dd, 1H), 7.93 (m, 1H), 7.81 (d, 2H), 7.50 (td, 1H), 7.32-7.52(m, 5H), 4.00 (d, 1H), 3.51-3.60 (m, 2H), 3.01 (dd, 1H), 2.83 (dd, 1H).

General synthesis of8-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]Pyrimidine Derivatives ofGeneral Formula [F-014] Scheme A5

8-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F-014] were prepared by reaction of a 4-Substituted8-Chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin derivatives of generalformula [F-010] in a Buchwald type reaction utilising a suitable amine,of general formula [F-015], a palladium catalyst such as Pd(dba)₂ orPd(OAc)₂, a ligand such as Xantphos and a base such as NaOtBu or Cs₂CO₃in a polar solvent such as dioxane or a combination of dioxane and DMAat high temperature either by heating thermally or using a microwavereactor. After reaction work up, typically by a liquid-liquid extractionor purification by acidic ion exchange catch-release, the intermediatewas purified by column chromatography and the N-Boc derivatives weredeprotected under acidic conditions with a strong acid such as TFA, HClin a solvent such as DCM, DCE or 1,4-dioxane or by catch and releasesulfonic acidic resins such as polymer supported toluene sulfonic acidand the crude reaction product was purified by normal phasechromatography or reverse phase preparative HPLC.

Synthesis ofN⁴—((R)-2-Amino-3-phenyl-propyl)-N⁸-phenyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine-4,8-diamine[123]

N⁴—((R)-2-Amino-3-phenyl-propyl)-N⁸-phenyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine-4,8-diamine[123]

In a microwave vial,[(S)-1-Benzyl-2-(8-chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [A059](0.05 g 0.1 mmol) Aniline (0.015 g, 0.15mmol), Pd(dba)₂ (0.003 g, 0.005 mmol), Xantphos (0.006 g, 0.01 mmol),Sodium tert butoxide (0.02 g, 0.2 mmol) and dioxane (1.3 mL) were addedsuccessively. The microwave vial was heated under microwaves (150° C.,10 min). The solvent was then removed under reduced pressure, DCM (2 mL)and TFA (0.5 mL) were added successively and the solution was stirred3h. The solution was poured on a SCX2 column and was washed with MeOH.The compound was released using a 2M NH3/MeOH solution, and then wasconcentrated under reduce pressure. The crude was purified bypreparative HPLC (method A) to yield the title compound [123]: LCMSmethod: 1, RT:3.53 min, MI 448 [M+H]; NMR (1H, 300 MHz, d6-dmso): peaksmight be underneath solvent peaks at 2.5 and 3.3 ppm. 9.35 (s, 1H), 8.71(d, 2H), 8.35 (d, 2H), 8.03-8.08 (m, 3H), 7.46 (d, 1H), 7.27-7.38 (m,7H), 7.02 (t, 1H), 3.86 (d, 1H), 2.70-2.78 (m, 2H).

The following compounds were synthesised according to the generalsynthesis shown in scheme [A5]:

Ex SM Amine Analysis Name 1124 [A059]

Method 1: RT: 2.16 min, MI: 450 [M + H] (1H, 300 MHz, d6-dmso): 8.70 (d,2H), 8.64 (d, 2H), 8.34 (s, 1H), 8.25 (d, 1H), 8.04 (d, 2H), 7.70 (d,1H), 7.40-7.33 (m, 5H), 7.10 (t, 1H), 3.97-3.92 (m, 1H), 3.58-3.50 (m,2H), 2.99-2.93 (m, 1H), 2.87-2.80 (m, 1H). 4-N-[(2S)-2-amino-3-phenylpropyl]-2-(pyridin- 4-yl)-8-N-(pyrimidin-2- yl)pyrido[3,4-d]pyrimidine-4,8-diamine 125 [A059]

Method 1: RT: 2.16 min, MI: 482 [M + H] 4-N-[(2S)-2-amino-3-phenylpropyl]-8-N-(3- chlorophenyl)-2-(pyridin- 4-yl)pyrido[3,4-d]pyrimidine-4,8-diamine 126 [A059]

Method 1: RT: 2.69 min, MI: 439 [M + H] 4-N-[(2S)-2-amino-3-phenylpropyl]-2-(pyridin- 4-yl)-8-N-(1H-1,2,4- triazol-3-yl)pyrido[3,4-d]pyrimidine-4,8-diamine

General synthesis of8-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofGeneral Formula [F-014] Scheme A6

8-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F-014] were prepared by reaction of a 4-Substituted8-Chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin derivative of generalformula [F-010] in a nucleophilic aromatic substitution type reactionutilising a suitable amine [method A], thiol [method B] or phenol[method C] of general formula [F-015], and a base such as NaH in a polaraprotic solvent such as DMA or DMF at high temperature either by heatingthermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the intermediate was purified by columnchromatography and the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, HCl in a solvent such as DCM,DCE or 1,4-dioxane or by catch and release sulfonic acidic resins suchas polymer supported toluene sulfonic acid and the crude reactionproduct was purified by normal phase chromatography or reverse phasepreparative HPLC.

Synthesis of(R)—N-[8-(4-Methyl-piperazin-1-yl)-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine[127]

(R)—N¹-[8-(4-Methyl-piperazin-1-yl)-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl]-3-phenyl-propane-1,2-diamine[127]

A microwave vial was charged with[(S)-1-Benzyl-2-(8-chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [A059](0.07 g, 0.142 mmol), N-methylpiperazine(0.031 mL, 0.285 mmol) and DMA (2 mL). The solution was heated undermicrowaves (150° C., 10 min). 2 other equivalent of N-methylpiperazine(0.031 mL, 0.285 mmol) was added and the vial was heated again undermicrowaves (150° C., 10 min). The solvent was removed under reducedpressure and DCM (2 mL) and TFA (0.5 mL) were added successively. Thesolution was stirred 3h and then was poured on a SCX-2 column, washedwith MeOH and the expected product was released using a solutionMeOH/NH3 2M. The crude was then purified by preparative HPLC (method A)to yield the title compound [127]: LCMS method: 1, RT:1.55 min, MI 455[M+H]; NMR (1H, 300 MHz, d6-dmso): 9.17 (brs, 1H), 8.86 (d, 2H), 8.30(s, 3H), 8.10 (d, 1H), 7.86 (d, 2H), 7.48 (d, 1H), 7.35-7.41 (m, 5H),3.83-4.04 (m, 5H), 3.66-3.76 (m, 1H), 3.54-3.64 (m, 1H), 3.12 (dd, 1H),2.86 (dd, 1H), 2.67-2.72 (m, 4H), 2.53 (s, 3H).

Synthesis of(R)-3-Phenyl-N¹-(8-phenylsulfanyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-propane-1,2-diamine[128]

(R)-3-Phenyl-N¹-(8-phenylsulfanyl-2-pyridin-4-yl-pyrid o[3,4-d]pyrimidin-4-yl)-propane-1,2-diamine[128]

To a suspension of NaH (60% in mineral oil, 0.008 g, 0.2 mmol) in DMF (2mL), Thiophenol (0.02 g, 0.185 mmol) was added. The mixture was stirred1h and[(S)-1-Benzyl-2-(8-chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [A059](0.07 g, 0.142 mmol) was added. The mixturewas stirred overnight and water (0.3 mL) was added. The solvent wereremoved under reduced pressure and DCM (2 mL) and TFA (0.5 mL) wereadded successively. The solution was stirred 3h and then was poured on aSCX-2 column, washed with MeOH and the expected product was releasedusing a solution MeOH/NH3 2M. The crude was then purified by preparativeHPLC (method A). To yield the title compound [128]: LCMS method: 1,RT:4.06 min, MI 465 [M+H]; NMR (1H, 300 MHz, d6-dmso): 9.38 (brs, 1H),8.72 (d, 2H), 8.23 (s, 3H), 8.03 (d, 2H), 7.89 (d, 1H), 7.58-7.61 (m,2H), 7.36-7.47 (m, 6H), 3.98 (d, 1H), 3.56-3.73 (m, 2H), 3.05 (dd, 1H),2.87 (dd, 1H).

The following compounds were synthesised according to the generalsynthesis shown in scheme [A6]:

Meth- Ex od SM Nuc Analysis Name 129 B [A059]

Method 1: RT: 3.39 min, MI: 449 [M + H] (1H, 300 MHz, d6-dmso): 9.43(brs, 1H), 8.68 (d, 2H), 8.29 (s, 2H), 8.03 (d, 1H), 7.99 (d, 2H), 7.85(d, 1H), 7.36-7.48 (m, 6H), 7.21-7.28 (m, 3H), 4.00 (d, 1H), 3.58-3.55(m, 2H), 3.06 (dd, 1H), 2.81-2.93 (m, 1H), N-[(2S)-2-amino-3-phenylpropyl]-8- phenoxy-2-(pyridin- 4-yl)pyrido[3,4-d]pyrimidin-4-amine 130 C [A059]

Method 1: RT: 3.43 min, MI: 403 [M + H] (1H, 300 MHz, d6-dmso): 9.58(brs, 1H), 8.69 (d, 2H), 8.42 (d, 1H), 8.32 (s, 2H), 7.94 (d, 2H), 7.81(d, 1H), 7.36-7.45 (m, 5H), 3.99 (d, 1H), 3.59-3.70 (m, 2H), 3.07 (dd,1H), 2.81 (dd, 1H), 2.53 (s, 3H). N-[(2S)-2-amino-3- phenylpropyl]-8-(methylsulfanyl)-2- (pyridin-4- yl)pyrido[3,4- d]pyrimidin-4-amine

Synthesis of4-(4-{[(2S)-2-amino-3-phenylpropyl]amino}-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-8-yl)-2-methylbut-3-yn-2-ol[131]

4-(4-{[(2S)-2-amino-3-phenylpropyl]amino}-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-8-yl)-2-methylbut-3-yn-2-ol[131]

A microwave vial was charged with[(S)-1-Benzyl-2-(8-chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [A059](0.05 g, 0.1 mmol), Pd(PPh₃)₂Cl₂ (0.007 g,0.01 mmol), CuI (0.002 g, 0.1 mmol), 2-methyl-3-butyn-2-ol (0.035 g,0.037 mmol), Triphenylphosphine (0.005 g, 0.02 mmol), Triethylamine (0.2mL) and DMF (0.8 mL). The vial was heated under microwave (150° C., 10min). The solvent was removed under reduced pressure and DCM (2 mL) andTFA (1 mL) were added and the mixture was stirred 3h. The solution waspoured on a SCX2 column and was washed with MeOH. The compound wasreleased using a 2M NH3/MeOH solution, and then was concentrated underreduce pressure. The crude was purified by preparative HPLC (method A)to yield the title compound [131]: LCMS method: 1, RT:3.12 min, MI 439[M+H]; NMR (1H, 300 MHz, d6-dmso): 8.71 (d, 2H), 8.56 (d, 1H), 8.31(brs, 1H), 8.15 (d, 1H), 8.08 (d, 2H), 7.41-7.31 (m, 5H), 3.97-3.92 (m,1H), 3.59-3.50 (m, 2H), 2.99-2.90 (m, 1H), 2.86-2.79 (m, 1H), 1.59 (s,6H).

General Synthesis of Substituted5-Substituted-1-Yl-2-Pyridin-4-Yl-Pyrido[3,4-d] Pyrimidine Derivativesof General Formula [F-001] Scheme A7

2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives of generalformula [F-004] were prepared by coupling of a ortho-halo-isonicotinicacid derivative of general formula [F-016] with an appropriatelysubstituted 4-carbamimidoyl-pyridines of general formula [F-018] with asuitable coupling agent such asO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in a polar aprotic solvent such as DMA orDMF. The isonicotinoyl-amidine derivative of general formula [F-017]were then cyclised to displace the relevant halogen group to yield thedesired 2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives ofgeneral formula [F-004].4-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F-001] were prepared by the reaction of a2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives of generalformula [F-004] with a chlorinatation agent such as phosphorousoxychloride and the intermediate 4-chloro derivative was then reactedwith primary or secondary amino derivative of general formula [F-015],in a polar aprotic solvent such as DMA, DMF, NMP in the presence of atertiary amine base such as Et₃N, DIPEA or NMM at ambient temperature[method A]. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, theN-Boc derivatives were deprotected under acidic conditions with a strongacid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in a solventsuch as DCM, DCE, THF, EtOH or MeOH and the crude reaction product waspurified by normal phase silica gel chromatography or reverse phasepreparative HPLC.4-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F-001] were prepared by the reaction of a2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives of generalformula [F-004] with 2,4,6-triisopropylbenzenesulfonyl chloride in apolar aprotic solvent such as DMA, DMF, NMP with a tertiary alkylaminebase such as Et₃N, DIPEA or NMM and a catalytic amount of DMAP [methodB]. The intermediate 6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester was then reactedwith a primary or secondary amino derivative, of general formula[F-015], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, theN-Boc derivatives were deprotected under acidic conditions with a strongacid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in a solventsuch as DCM, DCE, THF, EtOH or MeOH and the crude reaction product waspurified by reverse phase preparative HPLC.

Synthesis of5-Chloro-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine[132]

Synthesis of 3,5-Dichloro-N-(imino-pyridin-4-yl-methyl)-isonicotinamide[A060]

3,5-Dichloro-isonicotinic acid (10.4 mmol, 1.997 g), was dissolved inanhydrous DMF (50 mL) at room temperature and HATU (10.4 mmol, 3.95 g),added in one portion and the mixture stirred for 5 mins. Then DIPEA(28.6 mmol, 5.0 mL) was added in one portion and reaction stirred for 40minutes. Pyridine-4-carboximidamide hydrochloride (9.52 mmol, 1.5 g) wasadded in one portion and reaction stirred at room temperature for 18hours.

The reaction mixture was then poured into water (˜250 mL in totalincluding rinses of reaction vessel) in a conical flask. The resultantmixture was stirred at room temperature for 90 minutes and theprecipitate formed was filtered, washed with water (×2) and ether (×2).Then the solid was dried in vac oven for 4 hrs to yield the titlecompound [A060] (2.359 g), as a pale brown powder. LCMS method: 1,RT:3.31 min, MI 295 [M+H].

Synthesis of 5-Chloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[A061]

In a 25 mL Biotage microwave vessel, under nitrogen, was added3,5-Dichloro-N-(imino-pyridin-4-yl-methyl)-isonicotinamide [A060](1.5mmol, 0.443 g), cesium carbonate (3.0 mmol, 0.978 g) andN,N′-Dibenzylethylenediamine (0.3 mmol, 0.071 mL). The mixture wasstirred in anhydrous DMA (10 mL), vigorously and iron (III) chloride(0.15 mmol, 0.024 g) added in one portion. Then the mixture was heatedin the microwave at 120° C. for 90 mins. The reaction was allowed tocool to room temperature and acetic acid (12.0 mmol, 0.69 mL), addeddropwise over about 5 minutes and the resulting mixture diluted withMeOH (10 mL) and stirred at RT for 30 mins. The mixture was added to a10 g SCX-2 cartridge and washed with methanol (˜25-30 mL). The cartridgewas then washed with ammonia (2N in MeOH, 40 mL) and the ammonia washesconcentrated in vacuo to yield5-Chloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one (130 mg). Thenon-basic methanol washes of the SCX-2 cartridge were left standingovernight, forming a precipitate. This was filtered, washed withmethanol (×1), and dried in a vacuum oven overnight to yield the titlecompound [A061] (13 mg) as an off-white solid. LCMS method: 1, RT:2.12min, MI 259 [M+H].

Synthesis of4-(5-Chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A062]

5-Chloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [A061](0.553mmol, 0.143 g), was suspended in anhydrous DCM (14 mL) at RT undernitrogen and triethylamine (1.38 mmol, 0.193 mL), DMAP (approximately0.005 g) and 2,4,6-triisopropylbenzene sulfonyl chloride (0.663 mmol,0.201 g) were added sequentially. The reaction was stirred at roomtemperature as an off-white suspension for 2 hrs. Slowly the mixturebecomes a pale green suspension, that was left stirring overnight. Thenpyridine (4 mL) was added and the reaction vessel sonicated for 5minutes to try to improve the dissolution causing the reaction to changecolour from green to brown suspension. The resultant mixture was stirredat room temperature for 1 hour. Boc-piperazine (0.608 mmol, 0.113 g) wasadded in one portion and the mixture left stirring for 18 hours.

The reaction was diluted with water and extracted with DCM (×3).Combined organics washed with brine (×1), dried (MgSO₄), filtered andconcentrated in vacuo. To yield the title compound [A062] which was usedin the next reaction without further purification: LCMS method: 1,RT:5.69 min, MI 427 [M+H].

Synthesis of5-Chloro-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine[132]

To a solution of4-(5-Chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A062](0.47 mmol, 0.201 g), in anhydrous DCM (8mL), at room temperature was added HCl (4.0N in dioxane, 2 mL) to yieldan orange suspension that was stirred at room temperature for 3 hours.The mixture was then concentrated in vacuo, redissolved in DCM/MeOH(1:1, 6 mL total) and added to an SCX-2 10 g cartridge. The cartridgewas washed with DCM and MeOH (˜35 mL total ˜2:3 ratio respectively).Then the cartridge was washed with ammonia in methanol (2N, 40 mL) andthe ammonia washes were concentrated in vacuo to yield 92 mg brown oil.The crude material was purified by column chromatography (SP1 4 g VWRcolumn with 0-20% MeOH/DCM 15 volumes) to yield the title compound [138](0.044 g) as an orangey-yellow foam. LCMS method: 1, RT:1.60 min, MI 327[M+H]; NMR: (1H, 300 MHz, d6-dmso); 9.15 (1H, s), 8.77 (2H, d), 8.61(1H, s), 8.29 (2H, d), 3.69 (4H, br s), 2.85 (4H, br s)

Synthesis of 5,8-Dichloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[A063]

2,3,5-Trichloro-N-(imino-pyridin-4-yl-methyl)-isonicotinamide [A064] wasprepared by reaction of 2,3,5-Trichloro-isonicotinic acid,pyridine-4-carboximidamide hydrochloride, HATU, DIPEA and DMF at roomtemperature to give the title compound. LCMS method: 1, RT:4.37 min, MI330 [M+H]; NMR: (1H, 300 MHz, d6-dmso); 10.24 (1H, br s), 10.14 (1H, brs), 8.75 (2H, d), 8.60 (1H, s), 7.89 (2H, d).

5,8-Dichloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [A063] wasprepared by reaction of2,3,5-Trichloro-N-(imino-pyridin-4-yl-methyl)-isonicotinamide[A064],FeCl₃, Ce₂CO₃, HCl (4N in dioxane) and DMA in a in wave for 2 hrs at120° C. The reaction mixture was cooled and water (0.5 mL) was addedfollowed by MeOH (2 mL) and HCl (4 eq wrt carbonate, 2.4 mmol, 0.6 mL 4NHCl in dioxane) and the mixture was stirred for 10 mins. The yellowprecipitate was collected by filtration and the solid was washed withMeOH (2×, 2 mL) then dried in vac oven to give the title compound as ayellow solid (51 mg, 56% yield): LCMS method: 1, RT:4.80 min, MI 293[M+H]; NMR: (1H, 300 MHz, d6-dmso); 13.36 (1H, br s), 8.92 (2H, d), 8.49(1H, s), 8.14 (2H, br d).

Synthesis of3-Bromo-5-fluoro-N-(imino-pyridin-4-yl-methyl)-isonicotinamide [A065]

2-Bromo-5-fluoro-N-(imino-pyridin-4-yl-methyl)-isonicotinamide [A066]was prepare by reaction of 3-Bromo-4-carboxy-5-fluoro-pyridinium;chloride, pyridine-4-carboximidamide hydrochloride, HATU, DIPEA and DMFat room temperature to give the title compound. LCMS method: 1, RT:3.20min, MI 325 [M+H].

2-Bromo-5-fluoro-N-(imino-pyridin-4-yl-methyl)-isonicotinamide[A066](0.05 g, 0.155 mmol), DMA (0.5 mL), K₂CO₃ (0.022 g, 0.16 mmol),DIPEA (0.28 mL, 0.16 mmol) and DBA (0.024 mL, 0.16 mmol) wa heated at150° C. in wave for 45 mins. The crude reaction mixture was evapouratedunder reduced pressure and the crude material was purified by columnchromatography (SP1 4 g VWR column in 0.5% Et3N/DCM/0-20% MeOH) to yieldthe title compound [A065](0.044 g, 80% yield) as an orangey-yellow foam:LCMS method: 1, RT: 11.57 min, MI 304 [M+H].

The following compounds were synthesised according to the generalsynthesis shown in scheme [A7]:

Me- Amine Ex SM thod [F-015] Analysis Name 133 [A065] A

Method 1: RT: 1.77 min, MI: 373 [M + H] (1H, 500 MHz, d6-dmso), d6-dmso) 9.17 (1H, s), 8.77 (2H, dd), 8.72 (1H, s), 8.29 (2H, dd),3.78-3.61 (4H, m), 2.94 (2H, br s), 2.82-2.71 (2H, m)1-[5-bromo-2-(pyridin- 4-yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine 134[A063] A

Method 1: RT: 5.02 min, MI: 361 [M + H] (1H, 500 MHz, d6-dmso) 8.79 (2H,dd), 8.41 (1H, s), 8.30 (2H, dd), 3.74 (4H, br s), 2.98-2.75 (4H, m)1-[5,8-dichloro-2- (pyridin-4-yl)pyrido [3,4-d]pyrimidin-4-yl]piperazine

General Synthesis of Substituted5-Substituted-1-Yl-2-Pyridin-4-Yl-Pyrido[3,4-d] Pyrimidine Derivativesof General Formula [F-001] Scheme A8

Ortho-halo-isonicotinic acid derivatives of general formula [F-020] wereprepared by reaction of a dihalo isoinicotinic acid derivative ofgeneral formula [F-019] with a grindard reagent of general formula[F-021] in a polar aprotic solvent such as THF or Et₂O.2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives of generalformula [F-004] were prepared by coupling of a ortho-halo-isonicotinicacid derivative of general formula [F-020] with an appropriatelysubstituted 4-carbamimidoyl-pyridines of general formula [F-018] with asuitable coupling agent such as0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in a polar aprotic solvent such as DMA orDMF. The isonicotinoyl-amidine derivative of general formula [F-022]were cyclised to displace the relevant halogen group to yield thedesired-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives of generalformula [F-004].4-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F-001] were prepared by the reaction of a2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivative of general formula[F-004] with a chlorinatation agent such as phosphorous oxychloride andthe intermediate 4-chloro derivative was then reacted with primary orsecondary amino derivative of general formula [F-015], in a polaraprotic solvent such as DMA, DMF, NMP in the presence of a tertiaryamine base such as Et₃N, DIPEA or NMM at ambient temperature [method A].After reaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the N-Boc derivativeswere deprotected under acidic conditions with a strong acid such as TFA,TCA, methanesulfonic acid, HCl or H₂SO₄ in a solvent such as DCM, DCE,THF, EtOH or MeOH and the crude reaction product was purified by normalphase silica gel chromatography or reverse phase preparative HPLC.4-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F-001] were prepared by the reaction of a2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives of generalformula [F-004] with 2,4,6-triisopropylbenzenesulfonyl chloride in apolar aprotic solvent such as DMA, DMF, NMP with a tertiary alkylaminebase such as Et₃N, DIPEA or NMM and a catalytic amount of DMAP [methodB]. The intermediate 6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester was then reactedwith a primary or secondary amino derivative, of general formula[F-015], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, theN-Boc derivatives were deprotected under acidic conditions with a strongacid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in a solventsuch as DCM, DCE, THF, EtOH or MeOH and the crude reaction product waspurified by reverse phase preparative HPLC.

Synthesis of5-Butyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine[135]

Synthesis of 3-Butyl-5-fluoro-isonicotinic acid [A067]

3,5-Difluoro-isonicotinic acid (0.557 g, 3.5 mmol) was suspended inanhydrous THF (8 mL) at 0° C., under an atmosphere of nitrogen. To thiswas added butyl magnesium chloride (2.0 M in diethyl ether, 5.25 mL,10.5 mmol) dropwise over 10 minutes. The suspension slowly changed formduring the slow addition with preliminary agglomeration of solid thenthe solid started to dissolve slowly, achieving full solution aroundcompletion of addition of reagent. The reaction mixture was allowed towarm to room temperature and stirred over 72 hours to form a thickyellow suspension. Diluted with water and transferred into a single neckflask and concentrated in vacuo. The yellow solid was diluted with water(10 mL) and EtOAc (10 mL). The pH was adjusted pH-2, by dropwiseaddition of HCl (conc.) and extracted with EtOAc (×3—some of the yellowcolour goes into organics). Combined organics were washed with brine(×1), dried (MgSO₄) and concentrated in vacuo to yield the titlecompound [A067] as an orange gum/solid (0.402 g) that solidifies slowly:NMR: (1H, 300 MHz, d6-dmso); 8.52 (1H, s), 8.42 (1H, s), 2.67 (2H, t),1.58-1.48 (2H, m), 1.35-1.22 (2H, m), 0.87 (3H, t); LCMS method: 1,RT:1.22 min, MI 198 [M+H].

Synthesis of3-Butyl-5-fluoro-N-(imino-pyridin-4-yl-methyl)-isonicotinamide [A068]

3-Butyl-5-fluoro-isonicotinic acid [A067](2.05 mmol, 0.402 g) wasdissolved in anhydrous DMF (8 mL) and diisopropylethylamine (DIPEA)(5.95 mmol, 1.04 mL) was added and the mixture stirred at roomtemperature for 5 minutes. ThenO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (2.0 5 mmol, 0.78 g) was added in one portionand the resultant mixture stirred for 1 hour. pyridine-4-carboximidamidehydrochloride (1.95 mmol, 0.307 g) was then added portionwise over 5minutes to the reaction. The resultant solution was stirred at roomtemperature for 18 hours. The reaction mixture was poured into water (85mL) and stirred for 30 minutes and then extracted with EtOAc (×3). Thecombined organics washed with water (×4), brine (×1), dried (MgSO₄),filtered and concentrated in vacuo to yield the title compound [A068](480 mg) as a brown solid. The material was used crude in next reaction:NMR: (1H, 300 MHz, d6-dmso); 10.28 (1H, br s), 9.93 (1H, br s), 8.74(2H, d), 8.45 (1H, s), 8.37 (1H, s), 7.90 (2H, d), 2.72-2.66 (2H, m),1.58-1.48 (2H, m), 1.28-1.15 (2H, m), 0.79 (3H, t); LCMS method: 1,RT:3.90 min, MI 301 [M+H].

Synthesis of 5-Butyl-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[A069]

3-butyl-5-fluoro-N-(imino-pyridin-4-yl-methyl)-isonicotinamide [A068]was placed into 25 mL Biotage microwave vessel in solution in anhydrousDMA (5 mL) and heated at 150° C. in the microwave for 45 mins. Thereaction mixture was filtered material through an SCX-2 25 g cartridge.The cartridge was washed with methanol (50 mL). Then the cartridge waswashed with ammonia (2N, 40 mL) and the ammonia washes concentrated invacuo to yield the title compound [A069] (390 mg) as a pale brown solid:NMR: (1H, 300 MHz, d6-dmso); 8.95 (1H, s), 8.79 (2H, dd), 8.46 (1H, s),8.10 (2H, dd), 3.21 (2H, t), 1.63-1.50 (2H, m), 1.43-1.27 (2H, m), 0.91(3H, t)-also shows one equivalent of DMA; LCMS method: 1, RT:3.29 min,MI 281 [M+H].

Synthesis of 5-Butyl-4-chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine[A070]

5-Butyl-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [A069](1.35 mmol,0.378 g) was suspended in anhydrous 1,2-dichloroethane (DCE) (10 mL) andphosphorus oxychloride (POCl₃) (1.4 mmol, 0.131 mL) was added dropwiseover 2-3 minutes. Finally DIPEA (2.0 mmol, 0.348 mL) was added and themixture stirred at RT under nitrogen overnight. The brown solid slowlyto change appearance after POCl₃ addition, then darkens further onaddition of DIPEA to become a dark brown apparent solution. The reactionwas left stirring at room temperature overnight under nitrogen. After 20hours POCl₃ (65 μL) was added and stirred at room temperature overnight.The crude mixture was concentrated in vacuo, then azeotroped withtoluene (×2) to dryness. The residue was diluted with sodium carbonate(aq. soln., 2N, 20 mL) and extracted with DCM (×2), EtOAc (×1). Combinedorganics washed with brine (×1), dried (MgSO₄), filtered through a padof silica and concentrated in vacuo to yield the title compound [A070](180 mg) as a of a pale brown solid which was used in the next reactionwithout further purification: LCMS method: 1, RT:5.66 min, MI 299 [M+H].

Synthesis of4-(5-Butyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A071]

5-Butyl-4-chloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine [A070](0.615mmol, 0.180 g), was dissolved in anhydrous DCM (5 mL), under nitrogen atroom temperature and treated with triethylamine (0.868 mmol, 0.121 mL)and N-Boc-piperazine (0.682 mmol, 0.127 g) in one portion. The resultingmixture was stirred at room temperature for 2 hours. Then sodiumcarbonate (1N aq. soln, 20 mL) was added and extracted with DCM (×2) andEtOAc (×1). Combined organics washed with brine (×1), dried (MgSO₄),filtered and concentrated in vacuo to a dark brown solid, which waspurified by column chromatography (SP1 on 25 g VWR cartridge in 0-10%MeOH/DCM, 15 col vols) to yield the title compound [A071] as a brown gum(0.092 g) which was used in the next reaction without furtherpurification: NMR: (1H, 300 MHz, d6-dmso); 9.24 (1H, s), 8.79 (2H, d),8.49 (1H, s), 8.36 (2H, d), 3.77-3.48 (8H, m), 3.19-3.07 (2H, m),1.64-1.23 (4H, m), 1.48 (9H, s), 0.96-0.87 (3H, t)

Synthesis of5-Butyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine[135]

4-(5-Butyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A071](0.20 mmol, 0.09 g) was dissolved inanhydrous DCM (4 mL) and treated with hydrogen chloride (4N in dioxane,4 mL) at room temperature and stirred for 2 hours. The reaction wasdiluted with methanol and poured onto SCX-2 cartridge (5 g), washingwith MeOH/DCM (20 mL). The cartridge was then washed with ammonia (2N,20 mL) and the ammonia washes concentrated in vacuo to yield a brown gum(0.059 g). The residue was purified by column chromatography (SP1 4 gcolumn, in a gradient 5-20% MeOH/DCM 15col vols) to yield the titlecompound [133] as an orangey-brown gum (0.020 g).; NMR: (1H, 300 MHz,d6-dmso); 9.09 (1H, s), 8.76 (2H, d), 8.51 (1H, s), 8.31 (2H, d),3.73-3.58 (2H, br s), 3.50-3.37 (2H, br s), 3.07 (2H, t), 2.90-2.79 (4H,br s), 1.51-1.38 (2H, m), 1.28-1.15 μm (2H, m), 0.84 (3H, t); LCMSmethod: 1, RT:2.58 min, MI 349 [M+H].

The following compounds were synthesised according to the generalsynthesis shown in scheme [A8]:

Grig- SM nard Amine Ex [F-019] [F-021] [F-015] Analysis Name 136

EtMgBr

Method 1: RT: 1.64 min, MI: 321 [M + H] (1H, 300 MHz, d6-dmso), 9.08(1H, s), 8.76 (2H, dd), 8.54 (1H, s), 8.30 (2H, dd), 3.72-3.58 (2H, brs), 3.55-3.45 (2H, br s), 3.10 (2H, dd), 2.89-2.77 (4H, br s), 1.17 (3H,t) 1-[5-ethyl-2- (pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- yl]piperazine137

EtMgBr

Method 1: RT: 2.90 min, MI: 385 [M + H] (1H, 300 MHz, d6-dmso) 9.02 (1H,s), 8.72 (2H, dd), 8.42 (1H, s), 8.16 (2H, dd), 7.35-7.24 (5H, m), 3.91(1H, dd), 3.43 (1H, dd), 3.37-3.29 (1H, m), 3.21 (2H, dd), 2.83-2.70(2H, m), 1.33 (3H, t) N-[(2S)-2- amino-3- phenylpropyl]- 5-ethyl-2-(pyridin-4- yl)pyrido[3,4- d]pyrimidin-4- amine 138

MeMgBr

Method 1: RT: 3.93 min, MI: 307 [M + H] (1H, 300 MHz, d6-dmso) 9.06 (1H,s), 8.76 (2H, dd), 8.43 (1H, s), 8.30 (2H, dd), 3.57 (4H, br s), 2.84(4H, br s), 2.65 (3H, s) 1-[5-methyl-2- (pyridin-4- yl)pyrido[3,4-d]pyrimidin-4- yl]piperazine

General synthesis of substituted5-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F-001] Scheme A9

5-Substituted 2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives ofgeneral formula [F-004] were prepared by reaction of a 5-halosubstituted 2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives ofgeneral formula [F-024](prepared in scheme A7) in a palladium catalysedcross coupling reaction with a boronic acid or boronate ester derivativeof general formula [F-023] in the presence of a palladium catalyst suchas Pd(PPh₃)₄ or Pd(OAc)₂, and a base such as K₂CO₃ or Cs₂CO₃ in a polarsolvent such as dioxane or a combination of dioxane and DMA at hightemperature either by heating thermally or using a microwave reactor, ora palladium catalysed cross coupling reaction of a 5-halo substituted2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives of generalformula [F-024](prepared in scheme A7) with a fluoroborate derivative ofgeneral formula [F-025] in the presence of a catalyst such as Pd(PPh₃)₄or Pd(OAc)₂, a ligand such as RuPhos and a base such as K₂CO₃ or Cs₂CO₃in a polar solvent such as dioxane or a combination of dioxane and DMAat high temperature either by heating thermally or using a microwavereactor. 5-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidinederivatives of general formula [F-001] were prepared by the reaction ofa 5-substituted 2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivativesof general formula [F-004] with a chlorinatation agent such asphosphorous oxychloride and the intermediated 4-chloro derivative wasthen reacted with primary or secondary amino derivative of generalformula [F-015], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature [method A]. After reaction work up, typically by aliquid-liquid extraction or purification by acidic ion exchangecatch-release, the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, TCA, methanesulfonic acid,HCl or H₂SO₄ in a solvent such as DCM, DCE, THF, EtOH or MeOH and thecrude reaction product was purified by normal phase silica gelchromatography or reverse phase preparative HPLC.4-substituted-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine derivatives ofgeneral formula [F-001] were prepared by the reaction of a2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives of generalformula [F-004] with 2,4,6-triisopropylbenzenesulfonyl chloride in apolar aprotic solvent such as DMA, DMF, NMP with a tertiary alkylaminebase such as Et₃N, DIPEA or NMM and a catalytic amount of DMAP [methodB]. The intermediate 6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl ester was then reactedwith a primary or secondary amino derivative, of general formula[F-015], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, theN-Boc derivatives were deprotected under acidic conditions with a strongacid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in a solventsuch as DCM, DCE, THF, EtOH or MeOH and the crude reaction product waspurified by reverse phase preparative HPLC

Synthesis of1-[5-cyclopropyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine[139]

5-Cyclopropyl-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [A060]

5-Chloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [A061](0.670mmol, 0.173 g), potassium carbonate (2.01 mmol, 0.278 g) and cyclopropylboronic acid (1.34 mmol, 0.115 g) was suspended in anhydrous DMA (3 mL)and then subjected to vacuum/argon balloon sparge (×3). Thentetrakis(triphenylphosphine)palladium (0.067 mmol, 0.077 g) was added inone portion and the reaction vessel sealed and heated in a microwave at150° C. for 1 hr. The reaction was cooled to room temperature, undernitrogen. Potassium carbonate (2.0 mmol, 0.278 g) and cyclopropylboronic acid (1.34 mmol, 0.115 g) were added and the reaction mixturesubjected to vacuum/argon balloon sparge (×3). Thentetrakis(triphenylphosphine)palladium (0.067 mmol, 0.077 g) was added inone portion and the reaction vessel sealed and heated in a microwave at180° C. for 1 hr. The reaction was cooled to room temperature under airand left standing over 48 hours. The reaction mixture was then poured onto an SCX-2 cartridge (10 g) and washed with methanol (˜40 mL total).Then the cartridge was washed with ammonia (2N in MeOH, ˜40 mL) and theammonia washes concentrated in vacuo to yield the title compound [A072](78 mg) as a yellow solid which was taken through to next reactionwithout purification.

4-(5-Cyclopropyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A073]

A mixture of5-Cyclopropyl-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [A072](0.08g, 0.3 mmol), DIPEA (0.16 mL, 0.9 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (0.11 g, 0.36 mmol), DMAP (3 mg) and DMA (2 mL) wasstirred at room temperature under nitrogen and left to stir at at RT for2 hrs. Boc-piperazine (0.062 g, 0.33 mmol) was added and the mixture wasleft to stir at RT overnight. Water was added and the mixture wasextracted with EtOAc (×4). The extracts were combined washed with water(×4), brine, dried (MgSO4) and concentrated in vacuo. The crude reactionproduct was purified by flash column chromatography (SP1,EtOAc:cyclohexane elution) to yield the title compound [A073]: method:1, RT:5.57 min, MI 433 [M+H].

1-[5-cyclopropyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine[139]

A mixture of4-(5-Cyclopropyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A073](0.9 g, 0.2 mmol) in DCM (3 mL) and 4N HCldioxane (1 mL) was stirred at RT overnight. The crude reaction mixturewas evapourated under reduced pressure then dissolved in MeOH and washedonto SCX-2 (5 g) cartridge and washed with MeOH/DCM (1:1, ˜4 mL) thenMeOH (10 mL). Then eluted with ammonia (2N in MeOH, 15 mL). The Ammoniaelutent was concentrated in vacuo and the crude product was purified bynormal phase chromatography (SiO2, SP1 in MeOH (0-15%)/CHCl3) to givethe title compound [139](30 mg, 43% yield): LCMS method: 1, RT:1.65 min,MI 333 [M+H]; NMR: (1H, 300 MHz, d6-dmso); 8.99 (1H, s), 8.76 (2H, dd),8.30 (2H, dd), 8.09 (1H, s), 3.87-3.54 (4H, m), 2.87 (4H, br s),2.63-2.57 (1H, m), 1.24 (2H, ddd), 1.01 (2H, ddd)

Synthesis of5-Benzyloxymethyl-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [A074]

5-Benzyloxymethyl-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [A074]

A mixture of 5-Chloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[A061](0.1 g, 0.4 mmol), Potassium benzyloxymethyltrifluoroborate (0.1g, 0.45 mmol), cesium carbonate (0.4 g, 1.2 mmol) and RuPhos (12 mg,0.028 mmol) were placed in Biotage 5 mL vessel and suspended in dioxane(1.8 mL) and water (0.2 mL). The mixture was subjected to spurging withvacuum/argon (×3) then the Pd(OAc)₂ (3 mg, 0.014 mmol) was added and thevessel sealed and heated at 104° C. overnight. DMA (1 mL) was added andthe mixture was heated in wave at 150° C. for 1 hr. The RM was cooledand acetic acid (0.57 mL) was added and the mixture and stirred for 10mins. Then flushed down SCX-2 cartridge (10 g) washing with MeOH (30-40mL). Then washed with ammonia (2N in MeOH, 40 mL). Ammonia washesconcentrated in vacuo to yield the title compound [A074] which was usedwithout further purificatuion: method: 1, RT:3.31 min, MI 345 [M+H].

The following compounds were synthesised according to the generalsynthesis shown in scheme [A9]:

Me- Ex SM thod Amine Analysis Name 140 [A074] B

Method 1: RT: 4.78 min, MI: 413 [M + H] (1H, 500 MHz, d6-dmso), d6-dmso)9.18 (1H, s), 8.77 (2H, d), 8.69 (1H, s), 8.31 (2H, dd), 7.33-7.25 (5H,m), 4.99 (2H, s), 4.54 (2H, s), 3.51 (4H, br s), 2.79 (4H, t) 1-{5-[(benzyloxy)methyl]-2- (pyridin-4-yl)pyrido[3,4- d]pyrimidin-4-yl}piperazine

Synthesis of5-Chloro-4-piperazin-1-yl-8-(1H-pyrazol-3-yl)-2-pyridin-4-yl-pyrido[3,4-d]pyrmidine[141]

4-(5,8-Dichloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A075]

A mixture of 5,8-Dichloro-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[A063](0.43 g, 1.47 mmol) Et₃N (0.51 mL, 3.6 mmol), DCM (10 mL),pyridine (2 mL) was sonicated for 2 mins. Then DMAP (5 mg) was addedfollowed by 2,4,6-triisopropylbenzene sulfonyl chloride (0.53 g, 1.77mmol). The reaction mixture was left to stir at RT overnight. The darkbrown solution was diluted with water and extracted with DCM (×3) andEtOAc (×1). Combined organics washed with brine (×1). Brine re-extractedwith EtOAc (×1). Combined organics dried (MgSO4), filtered andconcentrated in vacuo. The crude material was purified by normal phasechromatography (SiO₂, [SP1 (25 g vwr cartridge, 0-10% MeOH/DCM]) to givethe title compound [A075](0.19 g, 28% yield): LCMS method: 1, RT:4.17min, MI 461 [M+H]; NMR: (1H, 300 MHz, d6-dmso); 8.81 (2H, d), 8.45 (1H,s), 8.33 (2H, d), 3.76 (4H, br s), 3.33 (4H, br s), 1.40 (9H, br s).

4-[5-Chloro-8-(1H-pyrazol-3-yl)-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [A076]

A mixture of4-(5,8-Dichloro-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A075](0.07 g, 0.15 mmol), potassium phosphatetribasic [K₃PO₄ 212.27 g/mol 21.2 g in 100 mL deionised water](0.3 mL,0.3 mmol), tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol),1H-Pyrazole-5-boronic acid (24 mg, 0.21 mmol) and DMA (1 mL) were heatedin μwave at 150° C. for 30 min. Acetic acid (0.52 mL) was added and themixture was left to stir at rt for 20 mins and then the crude productwas loaded onto an SCX cartridge and the cartridge was washed withmethanol then the product was eleuted with 2M ammonia/methanol. Theeluent was concentrated under reduced pressure and the crude reactionmixture was purified by normal phase chromatography (SiO₂, ethylacetate: cyclohexane elution) to give the title compound [A076]: LCMSmethod: 1, RT:5.62 min, MI 493 [M+H].

Chloro-4-piperazin-1-yl-8-(1H-pyrazol-3-yl)-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine[141]

A mixture of4-[5-Chloro-8-(1H-pyrazol-3-yl)-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [A076] and HCl dioxane (4N, 1 mL) was stirred atrt for 48 hours. The crude reaction mixture was evapourated underreduced pressure and the crude product loaded onto a SCX-2 cartridge (1g) and washed with methanol. The product was released from the cartridgeusing a solution of 2M ammonia/methanol. The ammonia/methanol eluent wasconcentrated under reduced pressure and the crude product was purifiedby preparative HPLC (method A) to yield to the title compound: LCMS:method: 1, RT:1.98 min, MI 393 [M+H];

NMR: (1H, 300 MHz, d6-dmso); 8.76-8.75 (3H, m), 8.50 (1H, s), 8.17 (2H,dd), 7.90 (1H, d), 6.67 μm (1H, dd), 3.76 (4H, br s), 2.93 (2H, br s),2.80 (2H, br s)

Synthesis of5-chloro-N,N-dimethyl-4-(piperazin-1-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-8-amine[142]

4-(5-Chloro-8-dimethylamino-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A077]

4-[5-Chloro-8-(1H-pyrazol-3-yl)-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [A075](0.046 g, 0.1 mmol), DMF (2 mL) anddimethylamine in ethanol (0.5 mL) was warmed to 50° C. in a sealedvessel and left to stir for 24 h. The crude reaction mixture wasevapourated under reduced pressure to yield the title compound [A077]which was used in the next step without further purification: LCMS:method: 1, RT:4.41 min, MI 470 [M+H].

5-chloro-N,N-dimethyl-4-(piperazin-1-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-8-amine[142]

A mixture of4-(5-Chloro-8-dimethylamino-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A077](0.1 g, 0.22 mmol), DCM (3 mL) and HCl (1 mLof a 4N solution in dioxane) was stirred at RT for 2 h. The crudereaction mixture was evpourated under reduced pressure then the crudeproduct was loaded onto an SCX cartridge and the cartridge was washedwith methanol then the product was eleuted with 2M ammonia/methanol. Theeluent was concentrated under reduced pressure and the crude reactionmixture was purified by normal phase chromatography (SiO₂, SP1 on 4 gcartridge in 0-15% MeOH/DCM) to give the title compound: LCMS: method:1, RT:5.40 min, MI 370 [M+H]; NMR: (1H, 300 MHz, d6-dmso); 8.73 (2H,dd), 8.22 (2H, dd), 7.97 (1H, s), 3.76-3.68 (2H, m), 3.56-3.49 (2H, m),3.16 (3H, s), 3.15 (3H, s), 2.95-2.87 (2H, m), 2.86.2-77 (2H, m)

Synthesis of5-Isopropenyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine[143]

Step 1: Synthesis of4-(5-Bromo-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A078]

A mixture of 5-Bromo-2-pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[A065](0.74 g, 2.45 mmol) in DMF (15 mL), DIPEA (1.3 mL, 7.3 mmol) andDMAP (5 mg) was stirred at rt for 10 min. 2,4,6-triisopropylbenzenesulfonyl chloride (0.89 g, 2.94 mmol) was added and the mixture was leftto stir at rt for 80 mins at RT, then boc-piperazine (0.5 g, 2.94 mmol)was added in one portion and the rm was left to stir at rt over night.Water (30 mL) was added and the mixture was stirred at RT for 20 mins.The resultant solid was collected by filtration and the crude productwas purified by column chromatography (SP1 (25 g cartridge) in 0-10%MeOH/DCM (˜20 vols, 4 vols at 10% MeOH/DCM)) to yield the title compound[A078](0.69 g, 60% yield): LCMS: method: 1, RT:5.83 min, MI 473 [M+H];NMR: (1H, 300 MHz, d6-dmso); 9.22 (1H, s), 8.78 (3H, m), 8.32 (2H, d),3.79 (4H, br s), 3.61 (4H, br s), 1.41 (9H, br s).

Step 2: Synthesis of4-(5-Isopropenyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A079]

4-(5-Bromo-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A078](0.2 mmol, 0.094 g), potassium phosphate(tribasic) (0.60 mmol, 0.127 g), and Isopropenylboronic acid pinacolester (0.30 mmol, 0.057 mL) were suspended in anhydrous dioxane (2 mL),in a 5 mL Biotage vessel under nitrogen. The vessel was subjected tovacuum/argon (balloon) sparge (×3) and thendichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.01 mmol, 0.008 g) added and the reactionsealed and warmed to 96° C. for 18 hours. The reaction mixture wascooled to room temperature under air, silica for chromatography added (1g) and the mixture concentrated in vacuo to a brown powder. This was dryloaded onto a silica cartridge and purified by chromatography (SP1 0-10%MeOH/DCM 15 col vols) to yield4-(5-Isopropenyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A079] (85 mg) as a 85 mg brown glass: NMR: (1H,500 MHz, CDCl₃); 9.31 (1H, s), 8.79 (2H, d), 8.50 (1H, s), 8.36 (2H, d),5.40 (1H, s), 5.32 (1H, s), 3.58 (8H, br s), 2.21 (3H, s), 1.24 (9H, s);LCMS: method: 1, RT:5.66 min, MI 433 [M+H].

Step 3: Synthesis of5-Isopropenyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine

To a solution of4-(5-Isopropenyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A079](0.105 mmol 0.045 g), in DCM (2 mL) at roomtemperature was added hydrogen chloride (4N in dioxane, 1 mL), to obtaina thick yellowy-brown suspension, that was stirred overnight. Thereaction mixture was then concentrated in vacuo, the residue redissolvedin MeOH and washed onto SCX-2 cartridge. The cartridge was washed withDCM and MeOH (1:1, 20 mL total). Then the SCX-2 was washed with ammonia(2N in MeOH, 15 mL). The combined ammonia washes were concentrated to anorangey-brown solid, which was purified by column chromatography (SP1 4g cartridge, 0-20% MeOH/DCM, 15 col vols) to yield5-Isopropenyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine[143](0.011 g) as a yellow glass: NMR: (1H, 500 MHz, d4-MeOH) 9.15 (1H, s),8.76 (2H, dd), 8.49 (1H, s), 8.31 (2H, dd), 5.40 (1H, s), 5.20 (1H, s),3.56 (4H, br s), 2.79 (4H, t), 2.17 (3H, s); LCMS: method: 1, RT:1.88min, MI 333 [M+H].LC-MS.

Example 1515-Methoxy-4-piperidin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine

151a) 3-tert-Butoxycarbonylamino-pyrrolidine-1,3-dicarboxylic acid1-(9H-fluoren-9-ylmethyl) ester:3-tert-Butoxycarbonylamino-pyrrolidine-3-carboxylic acid (1.50 g, 6.50mmol) was added to a solution of Sodium carbonate (1.65 g, 15.6 mmol) inWater (16.7 mL, 926 mmol) and 1,4-Dioxane (9 mL, 100 mmol). Theresulting solution was stirred and cooled in an ice bath. To thestirring reaction solution was added a solution of 9-Fluorenylmethylchloroformate (1.76 g, 6.82 mmol) in 1,4-Dioxane (13 mL, 160 mmol). Themixture was stirred at room temperature for 2 h, poured into Water (300mL) and extracted twice with ether. The aqueous phase was cooled in anice bath and slowly treated with 3 M of Hydrogen Chloride in Water (7.80mL, 23.4 mmol) to neutralize. The resulting mix was extracted with EtOAc(2×), the combined organics dried over Na2SO4, filtered, andconcentrated. The residue was pumped under high vacuum for 4 h, leaving3.12 g (106%) of foam, which was used for subsequent step withoutfurther manipulation.

151b) 3-tert-Butoxycarbonylamino-3-carbamoyl-pyrrolidine-1-carboxylicacid 9H-fluoren-9-ylmethyl ester: At rt Di-tert-Butyldicarbonate (655mg, 3.00 mmol) was added to a mixture of3-tert-Butoxycarbonylamino-pyrrolidine-1,3-dicarboxylic acid1-(9H-fluoren-9-ylmethyl) ester (905 mg, 2.00 mmol) and Pyridine (0.324mL, 4.00 mmol) in 1,4-Dioxane (5 mL, 60 mmol). After 15 minutes,Ammonium Bicarbonate (0.474 g, 6.00 mmol) was added, and the reactionmixture was stirred for 72 h. Added water (10 mL) to resulting solidmass and swirled. Filtered off solid and rinsed liberally with water.After air drying, dried resulting solid under high vacuum at rt.

Obtained 1.12 g (124%) of tannish solid. Proceeded and used this tannishsolid for subsequent step without further manipulation.

151c) (3-Carbamoyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester3-tert-Butoxycarbonylamino-3-carbamoyl-pyrrolidine-1-carboxylic acid9H-fluoren-9-ylmethyl ester (410 mg, 0.91 mmol) was suspended inMethanol (5 mL, 100 mmol), then at rt added Piperidine (1 mL, 10 mmol)neat. After 16 hours concentrated reaction under reduced pressure, thenpumped on residue under high vacuum overnight (to remove as muchpiperidine as possible), and used crude directly for subsequentreaction.

151d): 5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol (127 mg,0.501 mmol), Triethylamine (216 uL, 1.55 mmol),2,4,6-Triisopropylbenzenesulfonyl Chloride (167 mg, 0.552 mmol), and4-Dimethylaminopyridine (6.9 mg, 0.057 mmol) in N,N-Dimethylformamide(2.0 mL, 26 mmol) were stirred at room temperature for 1 h. Gradualdissolution of starting material was observed, intermediate sulfonateobserved by hplc. (3-Carbamoyl-pyrrolidin-3-yl)-carbamic acid tert-butylester (126 mg, 0.550 mmol) was then added as a solution inN,N-Dimethylformamide and the reaction was stirred at room temperature.After 45 minutes concentrated reaction under reduced pressure, thenpartitioned residue between EtOAc and water. Took organic and washedwith 3 mL of IN HCl. Took aqueous solution, added small amount of DMSOand purified over two runs with preparative reverse phase HPLC. Combinedpurest fractions of each major product and lyophylized. Obtained 32 mg(14%) of yellow lyophilate of front runningmaterial[3-Carbamoyl-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamicacid tert-butyl ester (LC/MS: M+H=466.2). Also obtained 35 mg (22%) ofside product5-Methoxy-4-piperidin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine(LC/MS: M+H=322.1), which was generated from piperidine left over frompreparation of starting material (3-Carbamoyl-pyrrolidin-3-yl)-carbamicacid tert-butyl ester. Proceeded on with[3-Carbamoyl-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamicacid tert-butyl ester for subsequent reaction without furthermanipulation.

Example 1523-Amino-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidine-3-carboxylicacid amide

Added a solution of Trifluoroacetic Acid (1 mL, 10 mmol) in Methylenechloride (2 mL, 30 mmol) to[3-Carbamoyl-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamicacid tert-butyl ester (30 mg, 0.06 mmol) at rt. After 30 minutesconcentrated reaction mixture under reduced pressure, then to residuetriturate with Et2O to get a solid. Filtered solid and washed liberallywith Et2O. Obtained with 17 mg of title compound as a solid (LC/MS:+H=366.1).

Example 1533-Amino-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidine-3-carboxylicacid phenylamide

153a)3-tert-Butoxycarbonylamino-3-phenylcarbamoyl-pyrrolidine-1-carboxylicacid-9H-fluoren-9-ylmethyl ester:N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (575 mg,3.00 mmol) was added to a mixture of3-tert-Butoxycarbonylamino-pyrrolidine-1,3-dicarboxylic acid1-(9H-fluoren-9-ylmethyl) ester (905 mg, 2.00 mmol),1-Hydroxybenzotriazole (2.70E2 mg, 2.00 mmol) and Aniline (228 uL, 2.50mmol) in Tetrahydrofuran (25 mL, 310 mmol). After 10 minutes addedN,N-Dimethylformamide (10 mL, 100 mmol) to facilitate dissolution. After1.5 hour concentrated reaction mixture under reduced pressure. Theresidue was partitioned between EtOAc (2×) and saturated aqueous NaHCO3.The combined organic phases were dried over Na2SO4, filtered, andconcentrated under reduced pressure to yield 0.97 g (92%) of foam(LC/MS: M+H=528.1), which was used for subsequent step without furthermanipulation.

153b) (3-Phenylcarbamoyl-pyrrolidin-3-yl)-carbamic acid tert-butylester:3-tert-Butoxycarbonylamino-3-phenylcarbamoyl-pyrrolidine-1-carboxylicacid 9H-fluoren-9-ylmethyl ester (960 mg, 1.8 mmol) was combined withMethanol (10 mL, 200 mmol), then at toom temperature added Piperidine (2mL, 20 mmol) neat and the reaction was stirred for 72 h. Concentratedreaction mixture under reduced pressure and Obtained a solid mass.Triturated entire sample with Et2O, filtered and rinsed solid liberallywith Et2O. After air drying there remained 0.55 g (99%) of tannishsolid. Proceeded and used this material in subsequent reaction withoutfurther manipulation.

153c)[1-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-3-phenylcarbamoyl-pyrrolidin-3-yl]-carbamicacid tert-butyl ester:5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol (254 mg, 1.00mmol), Triethylamine (431 uL, 3.10 mmol),2,4,6-Triisopropylbenzenesulfonyl Chloride (334 mg, 1.10 mmol), and4-Dimethylaminopyridine (14 mg, 0.11 mmol) in N,N-Dimethylformamide (4.0mL, 52 mmol) were stirred at room temperature for 1 hour.(3-Phenylcarbamoyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (335mg, 1.10 mmol) was added neat and the reaction was stirred at roomtemperature overnight. The reaction was then concentrated under reducedpressure and partitioned residue between EtOAc and water. Had to filterbefore separating layers, as precipiated solid causing some problemsbetween layers. The organic phase was dried over Na2SO4, filtered, andconcentrated under reduced pressure to give 500 mg of crude product.Dissolved crude in DMSO (3.6 mL), filtered, and purified via preparativereverse phase HPLC. Took purest fractions and basified with saturatedaqueous NaHCO3. Solid which crashed from the solution was filtered, andrinsed with water. After air drying there remained 50 mg (9%) off whitesolid. (LC/MS: M+H=542.1). Proceeded and used material for subsequentstep without further manipulation.

153d) At rt dissolved[1-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-3-phenylcarbamoyl-pyrrolidin-3-yl]-carbamicacid tert-butyl ester (50.0 mg, 0.0923 mmol) in Methylene chloride (2.0mL, 31 mmol) then added Trifluoroacetic Acid (1.0 mL, 13 mmol) neat.After 2.5 h concentrated reaction under reduced pressure, dissolvedresidue in 0.80 mL DMSO, filtered, and purified via preparative reversephase HPLC. Combined and lyophilized purest fractions. Obtained 32 mg(78%) of title compound as a yellow lyophilate (LC/MS: M+H=442.1).

Example 1544-Amino-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperidine-4-carboxylicacid [(S)-1-(4-chloro-phenyl)-3-hydroxy-propyl]-amide

154a)4-tert-Butoxycarbonylamino-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperidine-4-carboxylicacid methyl ester: 5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol(254 mg, 1.00 mmol), Triethylamine (0.432 mL, 3.10 mmol),2,4,6-Triisopropylbenzenesulfonyl Chloride (334 mg, 1.10 mmol), and4-Dimethylaminopyridine (14 mg, 0.11 mmol) were combined inN,N-Dimethylformamide (2.0 mL, 26 mmol), and stirred at roomtemperature. After 45 minutes4-tert-Butoxycarbonylamino-piperidine-4-carboxylic acid methyl ester(284 mg, 1.10 mmol; Supplier=Oakwood) was added neat and stirredovernight. The reaction mixture was concentrated under reduced pressureand the residue partitioned between CH2Cl2 and water. The organic phasewas dried over Na2SO4, filtered, and concentrated under reducedpressure. Resulting 380 mg (77%) of residue was used for subsequentsteps without further manipulation.

154b)4-tert-Butoxycarbonylamino-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperidine-4-carboxylicacid: Combined a solution of Lithium hydroxide (180 mg, 7.5 mmol) inwater (3 mL, 200 mmol) to a solution of4-tert-Butoxycarbonylamino-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperidine-4-carboxylicacid methyl ester (370 mg, 0.75 mmol) in Methanol (10 mL, 200 mmol) atrt and let homogeneous solution stir at rt for 16 hours. After cooling,treated reaction mixture with 1 M of Hydrogen Chloride in Water (7.5 mL,7.5 mmol), then concentrated off most of MeOH, leaving mostly aqueous assolvent. Filtered resulting solid, then took aqueous filtrate andconcentrated. Obtained 292 mg. Added 2.5 mL of DMSO, filtered, thenpurified via preparative reverse phase HPLC, lyopylized purest fractionsto yield 45 mg (12%) of desired product as a yellow lyophilate, whichwas used for subsequent steps without further manipulation.

154c)[4-[(S)-1-(4-Chloro-phenyl)-3-hydroxy-propylcarbamoyl]-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamicacid tert-butyl ester:4-tert-Butoxycarbonylamino-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperidine-4-carboxylicacid (30.0 mg, 0.0624 mmol) was combined with N,N-Dimethylformamide (1mL, 10 mmol), then 1-Hydroxybenzotriazole (8.44 mg, 0.0624 mmol) and(S)-3-Amino-3-(4-chloro-phenyl)-propan-1-ol; hydrochloride (27.7 mg,0.125 mmol; Supplier=Oakwood) were added followed byN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (35.9 mg,0.187 mmol). After 3 hours concentrated reaction under reduced pressure,then partitioned residue between EtOAc and water. The organic was thenwashed with saturated aqueous NaHCO3, dried over Na2SO4, filtered andconcentrated. The crude residue was used for the subsequent step withoutfurther manipulation

154d) At rt dissolved[4-[(S)-1-(4-Chloro-phenyl)-3-hydroxy-propylcarbamoyl]-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamicacid tert-butyl ester (70 mg, 0.1 mmol) in Methylene chloride (2.0 mL)then added Trifluoroacetic Acid (1.0 mL, 13 mmol) neat. After 2 hoursconcentrated reaction under reduced pressure, dissolved residue in 1 mLDMSO, filtered, and purified via preparative reverse phase HPLC.Combined purest fractions and lyophylized overnight. Obtained 15 mg(20%) of title compound as a yellow lyophilate (LC/MS: M+H=548.1).

Example 1554-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-2-carboxylicacid methyl ester

155a)4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester:5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol (508 mg, 2.00mmol), Triethylamine (863 uL, 6.19 mmol),2,4,6-Triisopropylbenzenesulfonyl Chloride (668 mg, 2.20 mmol), and4-Dimethylaminopyridine (28 mg, 0.23 mmol) in N,N-Dimethylformamide (10mL) were stirred at room temperature for 2 hours. Gradual dissolution ofstarting material was observed and a considerable darkening of thesolution. Piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methylester (536 mg, 2.20 mmol) was added and the reaction was stirred at roomtemperature for two hours. Water was added, and the resulting solidproduct was collected by filtration, washed with water, and dried.Obtained 448 mg (47%) tan colored solid product, which was used forsubsequent steps without further manipulation).

155b) At room temperature (rt) dissolved4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester (50 mg, 0.1 mmol) in Methylenechloride (2.0 mL) then added Trifluoroacetic Acid (1.0 mL, 13 mmol)neat. After 2.5 hours concentrated reaction solution under reducedpressure, then dissolved residue in 1 mL of DMSO and purified viapreparative reverse phase HPLC. Combined desired fractions andlyophylized overnight. Obtained 23 mg (60%) of title compound as ayellow lyophilate (LC/MS: M+H=381.1).

Example 1564-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-2-carboxylicacid phenylamide

156a)4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-2-phenylcarbamoyl-piperazine-1-carboxylicacid tert-butyl ester: At rt4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1,2-dicarboxylicacid 1-tert-butyl ester (77.0 mg, 0.165 mmol) was combined withN,N-Dimethylformamide (3 mL), then 1-Hydroxybenzotriazole (22.3 mg,0.165 mmol), 4-Methylmorpholine (36.3 uL, 0.330 mmol) and Aniline (22.6uL, 0.247 mmol) were added followed byN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (94.9 mg,0.495 mmol). After two hours the reaction mixture was concentrated underreduced pressure, and the resulting residue partitioned between EtOAcand saturated aqueous NaHCO3. The organic phase was dried over Na2SO4,filtered and concentrated. The crude residue was dissolved in 0.95 mL ofDMSO, filtered, and purified via preparative reverse phase HPLC. Thedesired fractions were combined and lyophilized to yield 42 mg (47%) ofdesired product as a yellow lyophilate (LC/MS: M+H=542.2).

156b) Trifluoroacetic Acid (1 mL, 10 mmol) and Methylene chloride (2 mL,30 mmol) were combined with4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-2-phenylcarbamoyl-piperazine-1-carboxylicacid tert-butyl ester (42.0 mg, 0.0775 mmol) at rt. After 1.5 h thereaction solution was concentrated under reduced pressure, after whichthe resulting residue was dissolved in 1.3 mL of DMSO, filtered, andpurified via preparative reverse phase HPLC. The desired fractions werecombined and lyophylized overnight to yield 29 mg (85%) of titlecompound as a yellow lypohilate (LC/MS: M+H=442.1).

Example 1574-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-2-carboxylicacid benzylamide

157a)2-Benzylcarbamoyl-4-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester: At room temperature4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1,2-dicarboxylicacid 1-tert-butyl ester (77.0 mg, 0.165 mmol) was combined withN,N-Dimethylformamide (3 mL), then 1-Hydroxybenzotriazole (22.3 mg,0.165 mmol), 4-Methylmorpholine (36.3 uL, 0.330 mmol) and Benzylamine(27.0 uL, 0.247 mmol) were added followed byN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (94.9 mg,0.495 mmol). After 1.5 h the reaction mixture was concentrated underreduced pressure and the resulting residue partitioned between EtOAc andsaturated aqueous NaHCO3. The organic phase was dried over Na2SO4,filtered and concentrated. The crude residue was dissolved in 0.85 mL ofDMSO, filtered, then purified via preparative reverse phase HPLC. Thedesired fractions were combined and lyophilized to yield 48 mg (52%) ofdesired product as a yellow lyophilate (LC/MS: M+H=556.2).

157b) A solution of Trifluoroacetic Acid (1 mL, 10 mmol) and Methylenechloride (2 mL, 30 mmol) was combined with2-Benzylcarbamoyl-4-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester (47.0 mg, 0.0846 mmol) at rt. After 1.5 hconcentrated mixture under reduced pressure, then dissolved residue in1.15 mL of DMSO, filtered, and purified via preparative reverse phaseHPLC. The desired fractions were combined and lyophilized to yield 38 mg(99%) of title compound as a yellow lypohilate (LC/MS: M+H=456.1).

Example 1584-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-2-carboxylicacid phenethyl-amide

158a)4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-2-phenethylcarbamoyl-piperazine-1-carboxylicacid tert-butyl ester: At rt4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1,2-dicarboxylicacid 1-tert-butyl ester (77.0 mg, 0.165 mmol) was combined withN,N-Dimethylformamide (3 mL, 30 mmol), then 1-Hydroxybenzotriazole (22.3mg, 0.165 mmol), 4-Methylmorpholine (36.3 uL, 0.330 mmol) andPhenethylamine (31.1 uL, 0.248 mmol) were added followed byN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (94.9 mg,0.495 mmol). After 16 h the reaction mixture was concentrated underreduced pressure and the resulting residue partitioned between EtOAc andsaturated aqueous NaHCO3. The organic phase was dried over Na2SO4,filtered and concentrated. The crude residue was dissolved in 0.9 mL ofDMSO, filtered, then purified via preparative reverse phase HPLC. Thedesired fractions were combined and lyophilized to yield 53 mg (56%) ofdesired product as a yellow lyophilate (LC/MS: M+H=570.2).

158b) A solution of Trifluoroacetic Acid (1 mL, 10 mmol) and Methylenechloride (2 mL) was combined with4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-2-phenethylcarbamoyl-piperazine-1-carboxylicacid tert-butyl ester (48.2 mg, 0.0846 mmol) at rt. After 1.5 hconcentrated mixture under reduced pressure, then dissolved residue in1.2 mL of DMSO, filtered, and purified via preparative reverse phaseHPLC. The desired fractions were combined and lyophilized to yield 38 mg(96%) of title compound as a yellow lyophilate (LC/MS: M+H=470.2).

Synthesis of4-(2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A080]

A mixture of 2-Pyridin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [A001](1.0g, 4.5 mmol), DMF (30 mL) and DIPEA (2.35 mL, 13.5 mmol) was stirred atroom temperature under nitrogen. DMAP (5 mg) was added followed by2,4,6-triisopropylbenzene sulfonyl chloride (1.64 g, 5.4 mmol) and themixture was left to stir for two hours. 1-Boc piperazine (0.83 g, 4.5mmol) was added and the mixture left to stri at room temperature overnight. Water (50 mL) was added and the mixture left to stir for 20 min,filtered and washed with water (×3). The solid was dissolved in DCM (50mL) and dried (MgSO4), filtered and evaporated under reduced pressure togive the title compound (1.2 g, 68% yield) which was used crude in thenext step without further purification.

Synthesis of4-(8-Propyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A081] and4-(8-Methyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A082]

To a solution of4-(2-Pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [A080](0.196 g, 0.5 mmol), butyraldehyde (0.090mL, 1.0 mmol), cone sulphuric acid (0.054 mL, 1.0 mmol) and ironsulphate heptahydrate (0.04 g, 0.15 mmol) in DMSO (5 mL) was addedhydrogen peroxide (35% solution in water, 0.146 mL, 1.5 mmol) dropwiseover 2 min. The reaction mixture was left to stir at room temperatureovernight then water (5 mL) was added and the mixture was basified byaddition of NaOH (1N) dropwise to pH ˜7-8. The mixture was thenextracted with DCM (×3) the organics were combined and washed with water(×1), brine (×1), dried (MgSO4), filtered and evaporated under reducedpressure. The crude residue was purified by column chromatography (SiO2column, ISCO eluting with 50-90% EtOAc/cHex on 120 g column) to give:4-(8-Propyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester (46 mg): LCMS: method: 5, RT:5.79 min, MI 435[M+H]; ¹H NMR (1H, CDCl3, 500 MHz), 8.77 (2H, dd), 8.50 (1H, d), 8.38(2H, dd), 7.46 (1H, d), 3.91-3.89 (4H, m), 3.71-3.69 (4H, m), 3.49 (2H,dd), 2.00-1.92 (2H, dq), 1.51 (9H, s), 1.09 (3H, t) and4-(8-Methyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester (44 mg) as a colourless glass: LCMS: method: 5,RT:5.11 min, MI 407 [M+H]; ¹H NMR (CDCl3, 500 MHz) 8.78 (2H, dd), 8.46(1H, d), 8.39 (2H, dd), 7.47 (1H, d), 3.91-3.89 (4H, m), 3.71-3.69 (4H,m), 3.09 (3H, s), 1.51 (9H, s).

Example 1594-Piperazin-1-yl-8-propyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine

A mixture of4-(8-Propyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid [A081](0.046 g, 0.105 mmol), DCM (3 mL) and HCl (4N in dioxane, 1mL) was stirred at room temperature for 90 min. The mixture wasevaporated under reduced pressure then the crude product was dissolvedin methanol and added to SCX-2 cartridge (10 g), washed with DCM/MeOH(1:1 10 mL) and MeOH (20 mL), then eluted with ammonia (7N in methanol,30 mL). The Ammonia washes were evaporated under reduced pressure togive the title compound (34 mg, 75% yield) as a yellow solid: LCMS:method: 5, RT:2.0 min, MI 335 [M+H]; ¹H NMR (d6-dmso, 500 MHz), 8.76(2H, dd), 8.45 (1H, d), 8.32 (2H, dd), 7.71 (1H, d), 3.89 (4H, t), 3.37(2H, t), 2.95 (4H, t), 1.86 (2H, dq), 0.99 (3H, t).

Example 1608-Methyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine

A mixture of4-(8-Methyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid [A082](0.045 g, 0.11 mmol), DCM (3 mL) and HCl (4N in dioxane, 1mL) was stirred at room temperature for 90 min. The mixture wasevaporated under reduced pressure then the crude product was dissolvedin methanol and added to SCX-2 cartridge (10 g), washed with DCM/MeOH(1:1 10 mL) and MeOH (20 mL), then eluted with ammonia (7N in methanol,30 mL). The Ammonia washes were evaporated under reduced pressure togive the title compound (29 mg, 75% yield) as a brown gum: LCMS: method:5, RT:2.17 min, MI 307 [M+H]; ¹H NMR (d6-dmso, 500 MHz), 8.76 (2H, dd),8.40 (1H, d), 8.33 (2H, dd), 7.70 (1H, d), 3.88 (4H, t), 2.94-2.92 (4H,m), 2.93 (3H, s)

General synthesis of substituted 2-amino pyridyl substituted2-(2-amino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl amine derivativesof general formula [G-003] Scheme B1

2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl amine derivativesof general formula [G-002] were prepared by the reaction of a2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol derivative ofgeneral formula [G-001] with 2,4,6-triisopropylbenzenesulfonyl chloridein a polar aprotic solvent such as DMA, DMF, NMP with a tertiaryalkylamine base such as Et₃N, DIPEA or NMM and a catalytic amount ofDMAP. The intermediate6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl ester wasthen reacted with a primary or secondary amino derivative, of generalformula [G-004], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. The 2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamine derivatives of general formula [G-002] was involved in a Buchwaldtype reaction utilising a suitable amine, of general formula [G-005], apalladium catalyst such as Pd(dba)₂ or Pd(OAc)₂, a ligand such asXantphos and a base such as NaOtBu or Cs₂CO₃ in a polar solvent such asdioxane or a combination of dioxane and DMA at high temperature eitherby heating thermally or using a microwave reactor, to yield substituted2-amino pyridyl substituted2-(2-amino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl amine derivativesof general formula [G-003].

After reaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the intermediate waspurified by column chromatography and the N-Boc derivatives weredeprotected under acidic conditions with a strong acid such as TFA, HClin a solvent such as DCM, DCE or 1,4-dioxane or by catch and releasesulfonic acidic resins such as polymer supported toluene sulfonic acidand the crude reaction product was purified by normal phasechromatography or reverse phase preparative HPLC.

Synthesis of[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine[200]

2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol [B001]

To a solution of 2-chloro-4-pyridinecarbonitrile (0.97 g, 7.03 mmol) inMeOH (35 mL) at RT, under nitrogen, was added NaOMe (0.08 g, 1.46 mmol)and left to stir for 60 mins. Then a solution of3-Amino-5-methoxy-isonicotinic acid (1 g, 5.86 mmol) in MeOH (15 mL) wasadded to the dark brown mixture dropwise over 5-10 mins (via syringe).The solution was stirred at rt for 2 h and then overnight at 85° C.After cooling down, the solid was filtered and, washed with methanol andused without further purification to yield the title compound[B001](0.97 g 57% yield:

LCMS: method: 5, RT:6.32 min, MI 287.34 [M+H].

4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyridol3,4-d]pyrimidin-4-yl-piperazine-1-carboxylicacid tert-butyl ester [B002]

A mixture of2-(2-chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol[B001](0.58 g, 2 mmol), anhydrous DMA (5 mL), triethylamine (0.58 mL, 4mmol) and DMAP (20 mg, 0.16 mmol) was sonicated for 10 min then stirredat room temperature for 10 min. 2,4,6-Triisopropyl-benzenesulfonylchloride (0.67 g, 2.2 mmol) was added and the mixture was sonicated for5 min then left to stir at room temperature for 2 hours. During thistime the material went into solution to form a viscous solution. Asolution of Boc piperazine (0.56 g, 3 mmol) in anhydrous DMA (1 mL) wasadded and the reaction mixture was left to stir at room temperatureovernight. Water (20 mL) was added and the reaction mixture wasextracted with DCM (2×30 mL), the extracts were combined and washed withwater (20 mL), saturated bicarbonate solution (2×20 mL) and water (20mL), dried (MgSO₄) filtered and evaporated under reduced pressure togive a pale yellow oil, which was purified by flash columnchromatography (SP1, 50 g SiO₂ cartridge 100% EtOAc up to 95% EtOAc: 5%MeOH gradient) to give the title compound [B002] as a colourless solid(0.22 g 24% yield). LCMS: method: 5, RT:10.86 min, MI 457 [M+H]; NMR:(1H, 500 MHz, CDCl₃); 9.0 (1H, s), 8.53 (1H, d), 8.35 (1H, s), 8.28 (1H,1H, d), 8.23 (1H, s), 3.70 (4H, br s), 3.64 (4H, br s), 1.50 (9H, s)

4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B003]

A mixture of4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B002](0.100 g, 0.22 mmol), Pd(dba)₂ (10 mg, 0.013mmol), Xantphos (17.5 mg, 0.025 mmol), NaOtBu (43 mg, 0.440 mmol) andanhydrous dioxane (4 ml) was added to a microwave vial. Aniline was thenadded the vial was sealed and heated at 150° C. for 20 min. Water (10mL) was added and the reaction mixture was extracted with DCM (2×10 mL),the extracts were combined and washed with water (10 mL), saturatedbicarbonate (2×10 mL) and water (10 mL), dried with MgSO4 filtered andevaporated to give a pale yellow oil, which was purified by flash columnchromatography (SP1, 25 g SiO2 cartridge 100% EtOAc up to 95% EtOAc: 5%MeOH gradient) to give the title compound [B003] as a colourless solid(0.04 g 36% yield). LCMS: method: 5, RT:7.80 min, MI 514 [M+H]; NMR:(1H, 500 MHz, CDCl₃); 8.93 (1H, s), 8.65 (1H, d), 8.41 (1H, s), 7.39(1H, d), 7.58 (5H, m), 6.55 (1H, br s), 3.63 (4H, m), 3.57 (4H, m), 1.49(9H, s).

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine

To a mixture of4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B003](0.040 g, 0.080 mmol) in DCM (1 ml) wasadded TFA (1 ml) and the mixture was left to stir at room temperaturefor 2 hours. After completion the crude reaction mixture was dilutedwith DCM (5 mL) and poured onto a 1 g SCX-2 cartridge and washed withDCM and MeOH before eluting with 2N NH3/MeOH which was evaporated togive a pale yellow oil, which was evaporated in a genevac to give a paleyellow solid (25 mg). LCMS: method: 5, RT:3.12 min, MI: 414.22 [M+H];NMR: (1H, 500 MHz, d6-dmso); 9.32 (1H, br s), 8.8 (1H, s), 8.29 (2H, m),7.88 (1H, s), 7.76 (2H, d), 7.64 (1H, d), 7.29 (2H, m), 6.88 (2H, m),4.04 (3H, s), 3.64 (4H, m), 2.88 (4H, m).

2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol [B004]

To a solution of 2-chloro-4-pyridinecarbonitrile (2.18 g, 15.77 mmol) indry THF (20 mL) was added 3-Amino-isonicotinic acid methyl ester (2 g,13.1 mmol) followed by Potassium tert-pentoxide (15.5 mL, 26.3 mmol 1.7Min toluene). The reaction was stirred overnight at RT. The precipitatewas collected by filtration to yield the title compound which was usedwithout further purification: LCMS: method: 5, RT:4.05 min, MI 259[M+H].

(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester [B005]

A mixture of 2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol[B003](1 g, 3.86 mmol), anhydrous DMA (10 mL), triethylamine (1.1 mL,7.73 mmol), 2,4,6-Triisopropylbenzenesulfonyl chloride (1.29 g, 3.25mmol), and DMAP (47 mg, 0.386 mmol) was stirred at room temperature for1 h and (R)-3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (940mg, 5.02 mmol) was added. The reaction mixture was stirred overnight andthe solvent was evaporated under reduced pressure. DCM and Et₂O wereadded and the resulting solid was collected and used without furtherpurification in the next step. LCMS: method: 5, RT 6.19 min, MI 427[M+H].

The following compounds were synthesised according to the generalsynthesis shown in scheme [B1](Example 1):

SM Analysis Ex [G-002] Amine Aniline LCMS NMR Name 201 [B003]

Method 1: RT: 1.91 min, MI: 416.17 [M + H] (1H, 300 MHz, CDCl₃) 10.22(1H, m), 9.16 (1H, m), 8.82 (1H, m), 7.72 (1H, m), 8.43 (1H, m), 8.33(1H, m), 8.30 (1H, m), 8.26 (1H, m), 7.85 (1H, m), 4.10 (3H, s), 3.71(4H, m), 2.96 (4H, m) [4-(5- Methoxy-4- piperazin-1- yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin- 2-yl]-pyrazin- 2-yl-amine 202 [B003]

Method 1: RT: 3.27 min, MI: 473.2 [M + H] (1H, 500 MHz, d6-dmso) 9.35(1H, s), 9.10 (1H, s), 8.91 (1H, s), 8.53 (1H, m), 8.46 (1H, d), 8.42(1H, s), 7.99 (1H, dd), 4.09 (3H, s), 3.93 (4H, m, br), 3.27 (4H, m, br)[4-5- Methoxy-4- piperazin-1- yl-pyrido[3,4- d]pyrimidin- 2-yl)-pyridin-2-yl]-(4- trifluoro- methyl- oxazol-2- yl)-amine 203 [B003]

Method 1: RT: 2.40 min, MI: 433.1 [M + H] (1H, 500 MHz, d6-dmso) 10.55(1H, s), 9.14 (1H, s), 8.81 (1H, s), 8.34 (1H, d), 8.31 (1H, s), 7.84(1H, d), 4.06 (3H, s), 3.68 (4H, m), 2.90 (4H, m), 2.19 (3H, s), 2.01(3H, s) (4,5- Dimethyl- oxazol-2-yl)- [4-(5- methoxy-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin- 2-yl)-pyridin- 2-yl]-amine 204 [B003]

Method 1: RT: 3.73 min, MI: 461.20 [M + H] (1H, 500 MHz, d6-dmso) 9.68(1H, s, br), 9.56 (2H, s, br), 8.96 (1H, s), 8.46 (1H, d), 8.42 (1H, s),8.23 (1H, s), 7.88 (1H, dd), 4.10 (3H, s), 3.96 (4H, m), 3.32 (1H, m),3.27 (4H, m), 0.86 (2H, m), 0.80 (2H, m) (4- Cyclopropyl- thiazol-2-yl)-[4-(5- methoxy-4- piperazin-1- yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin- 2-yl]-amine 205 [B003]

Method 1: RT: 3.47 min, MI: 439.2 [M + H] (1H, 300 MHz, d6-dmso) 9.82(1H, s), 9.10 (1H, s, br), 8.89 (1H, s), 8.41 (2H, s, br), 8.40 (1H, s),7.97 (1H, s), 7.89 (1H, d), 7.78 (1H, d), 7.48 (1H, t), 7.32 (1H, d),4.09 (3H, s), 3.90 (4H, m), 3.31 (4H, m) 3-[4-(5- Methoxy-4-piperazin-1- yl-pyrido[3,4- d]pyrimidin- 2-yl)-pyridin- 2-ylamino]-benzonitrile 206 [B003]

Method 1: RT: 2.69 min, MI: 482.03 [M + H] (1H, 300 MHz, d6-dmso) 8.95(1H, s), 8.79 (1H, s), 8.31 (1H, s), 8.23 (1H, d), 8.20 (1H, dt), 8.01(1H, s), 7.68 (1H, dd), 7.21 (1H, ddd), 7.14 (1H, td), 7.01-6.99 (1H,m), 4.06 (3H, s), 3.65 (4H, m, br), 2.87 (4H, m, br) (2-Fluoro-phenyl)-[4- (5-methoxy- 4-piperazin- l-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin- 2-yl]-amine 207 [B003]

(1H, 300 MHz, d6-dmso) 9.83 (1H, s), 8.85 (1H, s), 8.38 (1H, d), 8.36(1H, s), 7.98 (2H, s), 7.96 (1H, s), 7.76 (1H, d), 7.61 (2H, d), 4.07(3H, s), 3.79 (4H, m, br), 3.11 (4H, m, br) [4-(5- Methoxy-4-piperazin-1- yl-pyrido[3,4- d]pyrimidin- 2-yl)-pyridin- 2-yl]-(4-trifluoro- methyl- phenyl)- amine 208 [B003]

Method 1: RT: 3.51 min, MI: 338.2 [M + H] (1H, 300 MHz, d6-dmso) 8.78(1H, s), 8.30 (1H, s), 8.27 (1H, s), 8.04 (1H, d), 7.47 (1H, s), 7.41(1H, d), 6.10 (2H, s, br), 4.06 (3H, s), 3.66 (4H, m, br), 2.95 (4H, m,br) 4-(5- Methoxy-4- piperazin-1- yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin- 2-ylamine 209 [B003]

Method 1: RT: 1.80 min, MI: 465.2 [M + H] (1H, 300 MHz, d6-dmso) 10.11(1H, s), 9.10 (1H, s), 8.88 (1H, s), 8.47 (1H, d), 8.37 (1H, s), 8.05(1H, d), 4.08 (3H, s), 3.80 (4H, m, br), 3.64 (4H, t, br), 3.23 (2H, s),3.15 (4H, m, br), 2.55 (4H, m, br) N-[4-(5- Methoxy-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin- 2-yl)-pyridin- 2-yl]-2- morpholin-4-yl-acetamide 210 [B003]

Method 1: RT: 1.51 min, MI: 463.2 [M + H] (1H, 300 MHz, d6-dmso) 9.19(1H, s), 8.79 (1H, s), 8.41 (1H, d), 8.21 (1H, s), 8.10 (1H, d), 4.11(3H, s), 3.77 (4H, m), 3.19 (2H, s), 3.01 (4H, m), 2.59 (4H, m),1.73-1.69 (4H, m), 1.52 (2H, m) N-[4-(5- Methoxy-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin- 2-yl)-pyridin- 2-yl]-2- piperidin-1-yl-acetamide 211 [B003]

Method 1: RT: 2.05 min, MI: 416.14 [M + H] (1H, 300 MHz, d6-dmso) 10.42(1H, s), 8.85 (1H, s), 8.75 (2H, s), 8.45 (2H, d), 8.35 (1H, s), 8.22(1H, s), 7.90 (1H, dd), 4.08 (3H, s), 3.73 (4H, m), 2.98 (4H, m) [4-(5-Methoxy-4- piperazin-1- yl-pyrido[3,4- d]pyrimidin- 2-yl)-pyridin-2-yl]- pyrimidin-4- yl-amine 212 [B003]

Method 1: RT: 2.69 min, MI: 442.13 (1H, 300 MHz, d6-dmso) 9.17 (1H, s),8.85 (1H, s), 8.54 (1H, d), 8.33 (1H, s), 8.22 (1H, s), 8.09-8.05 (3H,m), 7.62-7.59 (1H, m), 7.54-7.51 (2H, m) N-[4-(5- Methoxy-4-piperazin-1- yl-pyrido[3,4- d]pyrimidin- 2-yl)-pyridin- 2-yl]- benzamide213 [B003]

Method 1: RT: 3.98 min, MI: 352.3 [M + H] (1H, 300 MHz, d6-dmso) 8.80(1H, s), 8.31 (1H, s), 8.11 (1H, d), 7.47 (1H, s), 7.39 (1H, d), 6.72(1H, d), 4.05 (3H, s), 3.71 (4H, m), 3.03 (4H, m), 2.81 (3H, d) [4-(5-Methoxy-4- piperazin-1- yl-pyrido[3,4- d]pyrimidin- 2-yl)-pyridin-2-yl]-methyl- amine 214 [B003]

Method 1: RT: 2.33 min MI: 380.18 [M + H] (1H, 300 MHz, d6-dmso) 10.58(1H, s), 9.05 (1H, s), 8.81 (1H, s), 8.43 (1H, d), 8.29 (1H, s), 7.97(1H, d), 4.05 (3H, s), 3.63 (4H, m), 3.15 (1H, d, br), 2.87 (4H, m),2.12 (3H, s) N-[4-(5- Methoxy-4- piperazin-1- yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin- 2-yl]- acetamide 215 [B003]

Method 1: RT: 3.87 min, MI: 395.11 [M + H] (1H, 300 MHz, d6-dmso) 10.58(1H, s), 9.05 (1H, s), 8.81 (1H, s), 8.43 (1H, d), 8.32 (1H, s), 7.98(1H, dd), 4.79 (1H, d), 4.06 (3H, s), 4.00 (1H, m, br), 3.81 (1H, m,br), 3.39 (3H, m, br), 2.12 (3H, s), 1.89 (2H, d, br), 1.56 (2H, m, br).N-{4-[4-(4- Hydroxy- piperidin-1- yl)-5- methoxy- pyrido[3,4-d]pyrimidin- 2-yl]-pyridin- 2-yl}- acetamide 216 [B003]

Method 1: RT: 2.66 min, MI: 406.13 [M + H] (1H, 300 MHz, d6-dmso) 8.28(1H, s), 8.01 (1H, s), 7.61 (1H, d), 7.42 (1H, s), 7.26 (1H, dd), 3.32(3H, s), 2.99 (4H, m), 2.27 (4H, m), 1.13 (1H, m), 0.22 (2H, m), 0.12(2H, m) Cyclopropane- carboxylic acid [4-(5- methoxy-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin- 2-yl)-pyridin- 2-yl]-amide 217 [B003]

Method 1: RT: 3.13 min, MI: 422.2 [M + H] (1H, 300 MHz, d6-dmso) 9.89(1H, s), 9.03 (1H, s), 8.84 (1H, s), 8.46 (1H, d), 8.33 (1H, s), 8.01(1H, dd), 4.06 (3H, s), 3.68 (4H, m, br), 2.95 (4H, m, br), 1.27 (9H, s)N-[4-(5- Methoxy-4- piperazin-1- yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin- 2-yl]-2,2- dimethyl- propionamide 218 [B003]

Method 1: RT: 2.82 min, MI: 450.20 [M + H] (1H, 300 MHz, d6-dmso) 10.59(1H, s), 9.10 (1H, s), 8.87 (1H, s), 8.46 (1H, d), 8.36 (1H, s), 8.01(1H, dd), 4.07 (3H, s), 3.90 (2H, dd, br), 3.78 (4H, m, br), 3.35 (2H,m), 3.13 (4H, m, br), 2.79 (1H, m), 1.74-1.66 (4H, m) Tetrahydro-pyran-4- carboxylic acid[4-(5- methoxy-4- piperazin-1- yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin- 2-yl]-amide 219 [B003]

Method 1: RT: 3.12 min, MI: 241.09 [M + H] (1H, 300 MHz, d6-dmso) 8.84(1H, s), 8.43 (1H, d), 8.35 (1H, s), 8.15 (1H, s), 7.82 (1H, dd), 7.40(1H, d), 7.01 (1H, s), 4.07 (3H, s), 3.75 (4H, m), 3.04 (4H, m) [4-(5-Methoxy-4- piperazin-1- yl-pyrido[3,4- d]pyrimidin- 2-yl)-pyridin-2-yl]-thiazol- 2-yl-amine 220 [B003]

Method 1: RT: 2.28 min, MI: 405.10 [M + H] (1H, 500 MHz, d6-dmso) 10.82(1H, s), 9.04 (1H, s), 8.84 (1H, s), 8.38 (1H, d), 8.34 (1H, s), 7.87(1H, d), 7.74 (1H, s), 7.09 (1H, s), 4.07 (3H, s), 3.74 (4H, m), 3.01(4H, m) [4-(5- Methoxy-4- piperazin-1- yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin- 2-yl]-oxazol- 2-yl-amine 221 [B003]

Method 1: RT: 2.44 min, MI: 419.18 [M + H] (1H, 500 MHz, d6-dmso) 10.77(1H, s), 9.19 (1H, s), 8.91 (1H, s), 8.40 (1H, s), 8.39 (1H, d), 7.88(1H, d), 7.44 (1H, s), 4.09 (3H, s), 3.92 (4H, m), 3.29 (4H, m), 2.10(3H, s) [4-(5- Methoxy-4- piperazin-1- yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin- 2-yl]-(4- methyl - oxazol-2-yl)- amine 222 [B003]

Method 1: RT: 2.38 min, MI: 444.2 [M + H] (1H, 500 MHz, d6-dmso) 9.39(1H, s), 8.88 (1H, s), 8.39 (1H, s), 8.31 (1H, d), 7.94 (1H, s), 7.75(2H, d), 7.68 (1H, d), 7.27 (2H, t), 6.89 (1H, t), 4.30 (2H, m), 4.09(3H, s), 3.70 (2H, m), 3.48-3.36 (5H, m) {(S)-4-[5- Methoxy-2- (2-phenylamino- pyridin-4-yl)- pyrido[3,4- d]pyrimidin- 4-yl]- piperazin-2-yl}-methanol 223 [B003]

Method 5: RT: 4.34 min, MI: 443.19 [M + H] (1H, 500 MHz, d6-dmso) 9.29(1H, s), 8.78 (1H, s), 8.30 (1H, s), 8.28 (1H, d), 7.89 (1H, d), 7.73(2H, d), 7.65 (1H, dd), 7.27 (2H, t), 6.88 (1H, t), 4.47 (1H, s), 4.06(3H, s), 3.94 (2H, m, br), 3.53 (2H, m), 1.64 (4H, m), 1.19 (3H, s)1-[5- Methoxy-2- (2- phenylamino- pyridin-4-yl)- pyrido[3,4-d]pyrimidin- 4-yl]-4- methyl- piperidin-4-ol 224 [B003]

Method 5: RT: 2.87 min, MI: 456.23 [M + H] (1H, 500 MHz, d6-dmso) 9.30(1H, s), 8.81 (1H, s), 8.32 (1H, s), 8.29 (1H, d), 7.88 (1H, s), 7.74(2H, d), 7.64 (1H, dd), 7.27 (2H, t), 6.89 (1H, t), 4.24-4.12 (2H, m),4.06 (3H, s), 3.15-3.06 (2H, m), 2.82 (2H, m), 2.59 (1H, m), 1.66 (1H,m), 0.96 (6H, dd) {4-[4-((S)-3- Isopropyl- piperazin-1- yl)-5- methoxy-pyrido[3,4- d]pyrimidin- 2-yl]-pyridin- 2-yl}-phenyl- amine 225 [B003]

Method 5: RT: 2.49 min, MI: 458.18 [M + H]] (1H, 500 MHz, d6-dmso) 9.30(1H, s), 8.82 (1H, s), 8.34 (1H, s), 8.29 (1H, d), 7.90 (1H, s), 7.73(2H, d), 7.67 (1H, dd), 7.27 (2H, t), 6.89 (1H, t), 4.21 (2H, m, br),4.06 (3H, s), 3.58 (2H, t), 3.22 (1H, t, br), 3.16-3.14 (2H, m), 2.95(2H, m), 1.63 (2H, m) 2-{(S)-4-[5- Methoxy-2- (2- phenylamino-pyridin-4-yl)- pyrido[3,4- d]pyrimidin- 4-yl]- piperazin-2- yl}-ethanol226 [B003]

Method 5: RT: 2.11 min, MI: 457.20 [M + H] (1H, 500 MHz, d6-dmso) 8.90(1H, s, br), 8.75 (1H, s), 8.32 (1H, s), 8.19 (1H, d), 8.07 (1H, d),7.78 (1H, s), 7.55 (1H, d), 7.47 (2H, d), 6.72 (2H, d), 4.76-4.70 (1H,m), 4.12 (3H, s), 3.29 (1H, dd), 3.10-3.02 (1H, m), 2.93-2.87 (1H, m),2.83 (6H, s), 2.32- 2.23 (1H, m), 1.90-1.76 (1H, m) N-{4-[5- Methoxy-4-((R)- pyrrolidin-3- ylamino)- pyrido[3,4- d]pyrimidin- 2-yl]-pyridin-2-yl}-N′,N′- dimethyl- benzene-1,4- diamine 227 [B003]

Method 5: RT: 2.53 min, MI: 499.26 [M + H] (1H, 500 MHz, d6-dmso) 9.23(1H, s, br), 8.75 (1H, s), 8.32 (1H, s), 8.28 (1H, d), 8.09 (1H, d),7.90 (1H, s), 7.65 (1H,d), 7.36 (1H, s), 7.22 (1H, s), 7.12 (1H, t),6.53 (1H, dd), 4.81- 4.75 (1H, m), 4.12 (3H, s), 3.75 (4H, m), 3.37-3.31 (1H, dd), 3.08 (4H, m), 2.95-2.90 (1H, m), 2.35-2.26 (1H, m), 1.88-1.82 (1H, m) {5-Methoxy- 2-[2-(3- morpholin-4- yl- phenylamino)-pyridin-4- yl]- pyrido[3,4- d]pyrimidin- 4-yl}-(R)- pyrrolidin-3-yl-amine 228 [B003]

Method 5: RT: 2.63 min, MI: 432.14 [M + H] (1H, 500 MHz, d6-dmso) 9.00(1H, s), 8.76 (1H, s), 8.33 (1H, s), 8.26 (1H, d), 8.16 (1H, t), 8.10(1H, d), 8.01 (1H, s), 7.71 (1H, d), 7.23 (1H, t), 7.14 (1H, t), 7.01(1H, t), 4.82-4.74 (1H, m), 4.13 (3H, s), 3.37-3.31 (1H, m), 3.12- 3.04(1H, m), 2.97-2.89 (1H, m), 2.35-2.25 (1H, m), 1.89-1.82 (1H, m){2-[2-(2- Fluoro- phenylamino)- pyridin-4- yl]-5- methoxy- pyrido[3,4-d]pyrimidin- 4-yl}-(R)- pyrrolidin-3- yl-amine 229 [B003]

Method 5: RT: 2.34 min, MI: 499.25 [M + H] (1H, 500 MHz, d6-dmso) 9.06(1H, s), 8.76 (1H, s), 8.33 (1H, s), 8.22 (1H, d), 8.09 (1H, d), 7.83(1H, s), 7.60 (1H, s), 7.58 (2H, d), 6.90 (2H, d), 4.81-4.74 (1H, m),4.13 (3H, s), 3.73 (4H, t), 3.02 (4H, t), 2.96-2.93 (2H, m), 2.33- 2.25(1H, m), 1.89-1.82 (1H, m) {5-Methoxy- 2-[2-(4- morpholin-4- yl-phenylamino)- pyridin-4- yl]-pyrido [3,4-d] pyrimidin- 4-yl}-(R)-pyrrolidin-3- yl-amine 230 [B003]

Method 5: RT: 2.48 min, MI: 432.14 [M + H] (1H, 300 MHz, d6-dmso) 9.46(1H, s), 8.78 (1H, s), 8.35 (1H, s), 8.32 (1H, s), 8.27 (1H, d), 8.15(1H, d), 7.89 (1H, s), 7.75 (2H, dd), 7.67 (1H, d), 7.11 (2H, t),4.88-4.84 (1H, m), 4.14 (3H, s), 3.49- 3.44 (1H, m), 3.21-3.16 (1H, m),3.07-3.02 (1H, m), 2.35-2.32 (1H, m), 1.99-1.94 (1H, m) {2-[2-(4-Fluoro- phenylamino)- pyridin-4- yl]-5- methoxy- pyrido[3,4-d]pyrimidin- 4-yl}-(R)- pyrrolidin-3- yl-amine 231 [B003]

Method 5: RT: 5.08 min, MI: 482.2 [M + H] (1H, 300 MHz, d6-dmso) 9.34(1H, s), 8.85 (1H, s), 8.36 (1H, s), 8.31 (1H, d), 7.89 (1H, s), 7.74(2H, d), 7.64 (1H, dd), 7.28 (1H, d), 7.24 (1H, s), 6.89 (1H, t), 4.23(1H, d), 4.07 (3H, s), 3.71-3.62 (1H, m), 3.22 (2H, dd), 3.08 (2H, d),2.89-2.81 (1H, m) {4-[5- Methoxy-4- (3- trifluoro- methyl- piperazin-1-yl)- pyrido[3,4- d]pyrimidin- 2-yl]-pyridin- 2-yl}-phenyl- amine 232[B003]

Method 5: RT: 2.68 min, MI: 453.17 [M + H] (1H, 300 MHz, d6-dmso) 9.28(1H, s), 8.82 (1H, s), 8.33 (1H, s), 8.29 (1H, d), 7.89 (1H, s), 7.75(2H, d), 7.67 (1H, d), 7.27 (2H, t), 6.89 (1H, t), 4.18 (1H, dd), 4.07(3H, s), 3.29 (1H, m), 3.12-3.02 (3H, m), 2.93 (1H, t), 2.82 (1H, t),2.71 (2H, d) {(S)-4-[5- Methoxy-2- (2- phenylamino- pyridin-4-yl)-pyrido[3,4- d]pyrimidin- 4-yl]- piperazin-2- yl}- acetonitrile 233[B003]

Method 5: RT: 2.43 min, MI: 446.18 [M + H] (1H, 300 MHz, d6-dmso) 9.30(1H, s), 8.81 (1H, s), 8.33 (1H, s), 8.29 (1H, d), 7.88 (1H, s), 7.73(2H, d), 7.65 (1H, d), 7.27 (1H, t), 6.89 (1H, t), 4.49 (1H, dd), 4.39(1H, dd), 4.15 (2H, t, br), 4.06 (3H, s), 3.15-3.11 (2H, m), 3.04 (1H,dd), 2.97 (1H, dd), 2.83 (1H, t, br), 2.60 (1H, m, br) {4-[4-((R)-3-Fluoromethyl- piperazin-1- yl)-5- methoxy- pyrido[3,4- d]pyrimidin-2-yl]-pyridin- 2-yl}-phenyl- amine 234 [B003]

Method 5: RT: 4.39 min, MI: 421.20 [M + H] (1H, 500 MHz, d6- dmso) 10.89(1H, s), 9.06 (1H, s), 8.80 (1H, s), 8.44 (1H, d), 8.31 (1H, s), 7.98(1H, d), 4.79 (1H, d), 4.06 (1H, s), 3.99 (2H, d, br), 3.80 (1H, m),3.38 (1H, m), 2.04 (1H, m), 1.89 (2H, d, br), 1.56 (2H, d, br),0.86-0.81 (4H, m) Cyclopropane- carboxylic acid {4-[4-(4- hydroxy-piperidin-1- yl)-5- methoxy- pyrido[3,4- d]pyrimidin- 2-yl]-pyridin-2-yl}-amide 235 [B003]

Method 5: RT: 2.43 min, MI: 446.18 [M + H] (1H, 500 MHz, d6-dmso) 9.30(1H, s), 8.81 (1H, s), 8.33 (1H, s), 8.29 (1H, d), 7.89 (1H, s), 7.73(2H, d), 7.65 (1H, d), 7.27 (2H, t), 6.89 (1H, t), 4.49 (1H, d, br),4.39 (1H, d, br), 4.15 (2H, t, br), 4.06 (3H, s), 3.13 (2H, m, br), 3.03(1H, d, br), 2.97 (1H, t, br), 2.83 (1H, t, br) {4-[4-((S)-3-Fluoromethyl- piperazin-1- yl)-5- methoxy- pyrido[3,4- d]pyrimidin-2-yl]-pyridin- 2-yl}-phenyl- amine 236 [B003]

Method 5: RT: 5.50 min, MI: 454.40 [M + H] (1H, 500 MHz, d6-dmso) 9.31(1H, s), 8.80 (1H, s), 8.32 (1H, s), 8.30 (1H, d), 7.88 (1H, s), 7.73(2H, d), 7.63 (1H, dd), 7.27 (2H, t), 6.89 (1H, t), 4.20 (1H, d, br),4.09 (1H, d, br), 4.04 (3H, s), 3.12 (1H, t), 3.00 (1H, d), 2.93 (1H,t), 2.73 (1H, t), 2.05 (1H, t), 0.76 (1H, m), 0.42 (2H, d, br), 0.28(2H, m) {4-[4-((S)-3- Cyclopropyl- piperazin-1- yl)-5- methoxy-pyrido[3,4- d]pyrimidin- 2-yl]-pyridin- 2-yl}-phenyl- amine 237 [B003]

Method 5: RT: 3.15 min, MI: 500.18 [M + H] (1H, 500 MHz, d6-dmso) 9.02(1H, s), 8.82 (1H, s), 8.33 (1H, s), 8.18 (1H, d), 7.84 (1H, s), 7.68(1H, dd), 7.30 (1H, m), 7.19 (1H, m), 4.48 (1H, d), 4.39 (1H, d), 4.18(1H, d, br), 4.12 (1H, m), 4.06 (3H, s), 3.13 (2H, m), 2.98 (2H, m),2.84 (1H, t, br) {4-[4-((R)-3- Fluoromethyl- piperazin-1- yl)-5-methoxy- pyrido[3,4- d]pyrimidin- 2-yl]-pyridin- 2-yl}-(2,3,6-trifluoro- phenyl)- amine 238 [B003]

Method 5: RT: 2.41 min, MI: 414 [M + H] (1H, 300 MHz, d6-dmso) 2.03 (m,1H), water peak very broad!!, 4.13 (s, 3H), 4.87 (brs, 1H), 6.89 (t,1H), 7.27 (t, 2H), 7.68 (d, 1H), 7.76 (d, 2H), 7.93 (s, 1H), 8.30 (d,1H), 8.35 (s, 1H), 8.79 (s, 1H), 9.44 (s, 1H) [5-Methoxy- 2-(2-phenylamino- pyridin-4-yl)- pyrido[3,4- d]pyrimidin- 4-yl]-(R)-pyrrolidin-3- yl-amine 239 [B003]

Method 5: RT: 2.10 min, MI: 416 [M + H] (1H, 300 MHz, d6-dmso) largewater peak . . . 4.84 (brs, 1H), 6.60 (brs, 1H), 7.90 (d, 1H), 8.12 (d,2H), 8.26 (d, 1H), 8.36 (s, 1H), 8.44 (d, 1H), 8.78 (d, 1H), 8.81 (s,1H), 9.11 (s, 1H), 10.30 (s, 1H) {5-Methoxy- 2-[2-(pyrazin- 2-ylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin- 4-yl}-(R)- pyrrolidin-3-yl-amine 240 [B003]

Method 5: RT: 3.23 min, MI: 448 [M + H] (1H, 300 MHz, d6-dmso) 1.92-2.05(m, 2H), huge water peak, 3.81 (s, 3H), 4.87 (brs, 1H), 7.22 (dd, 1H),7.91 (d, 1H), 8.11 (d, 1H), 8.19 (d, 1H), 8.26- 8.29 (m, 2H), 8.37 (s,1H), 8.55 (d, 1H), 8.83 (s, 1H), 9.16 (s, 1H), 11.07 (br s, 1H)Thiophene-2- carboxylic acid {4-[5- methoxy-4- ((R)- pyrrolidin-3-ylamino)- pyrido[3,4- d]pyrimidin- 2-yl]-pyridin- 2-yl}-amide 241 [B003]

Method 5: RT: 2.05 min, MI: 406.20 [M + H] (1H, 300 MHz, d6-dmso) 8.84(1H, s), 8.36 (1H, s), 8.09 (1H, d), 7.52 (1H, s), 7.37 (1H, dd), 6.79(1H, s), 4.18 (1H, m), 4.07 (3H, s), 3.87 (4H, m, br), 3.27 (4H, m, br),1.92 (2H, m, br), 1.69 (2H, m, br), 1.55-1.45 (4H, m). Cyclopentyl-[4-(5- methoxy-4- piperazin-1- yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin- 2-yl]-amine 242 [B003]

Method 5: RT: 2.18 min, MI: 420.23 [M + H] (1H, 500 MHz, d6-dmso) 8.79(1H, s), 8.31 (1H, s), 8.06 (1H, d), 7.49 (1H, s), 7.34 (1H, dd), 6.62(1H, d), 4.06 (3H, s), 3.74 (1H, m), 3.70 (4H, m), 3.01 (4H, m), 1.93(2H, d, br), 1.71 (2H, m), 1.58 (1H, m), 1.33-1.28 (2H, m), 1.20-1.16(3H, m) Cyclohexyl- [4-(5- methoxy-4- piperazin-1- yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin- 2-yl]-amine 243 [B003]

Method 5: RT: 1.84 min, MI: 386.0 [M + H] (1H, 500 MHz, d6-dmso): 10.32(1H, s), 9.20 (1H, s), 9.15 (1H, d), 8.79 (1H, d), 8.66 (1H, d),8.35-8.44 (2H, m), 8.29 (1H, s), 8.10 (1H, s), 7.92 (1H, d), 4.95 (1H,br s), 3.58 (1H, dd), 3.26 (3H, m), 2.35 (1H, m), 2.17 (1H, m). {2-[2-(Pyrazin-2- ylamino)- pyridin-4-yl]- pyrido[3,4- d]pyrimidin- 4-yl}-(R)-pyrrolidin-3- yl-amine

Synthesis of{1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol[244]

5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol[B006]

A mixture of 42-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol[B003](0.100 g, 0.346 mmol), Pd(OAc)₂ (4 mg, 0.018 mmol), Xantphos (21mg, 0.035 mmol), cesium carbonate (225 mg, 0.695 mmol) and anhydrousdioxane (1 ml) was heated at 900 overnight. Water (5 mL) was added andthe reaction mixture triturated for 30 min after which a yellow solidwas collected by filtration and washed with water (20 ml) and DCM (20ml) to give the title compound as a yellow solid (0.07 g, 59% yield)which was used without further purification in the next step. LCMSmethod: 1, RT:2.23 min, MI 346.24 [M+H]; NMR: (1H, 300 MHz, d6-dmso);9.30 (1H, s), 8.60 (1H, s), 8.25 (1H, d), 7.71 (2H, d), 7.65 (1H, s),7.45 (1H, dd), 7.26 (2H, t), 6.89 (1H, t), 3.96 (3H, s).

{1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol[244]

5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol[B003](70 mg, 0.203 mmol), TEA (84 μl, 0.609 mmol) and DMAP (25 mg,0.203 mmol) were sonicated in DMF (1.5 ml) for 30 min.2,4,6-Triisopropylbenzenesulfonyl chloride (74 mg, 0.243 mmol) was thenadded and the reaction mixture stirred at room temperature for 3 hr.4-Piperidinemethanol (28 mg, 0.243 mmol) was then added and the reactionmixture stirred at room temperature overnight. The solvent wasevaporated under reduced pressure to give a pale yellow solid, which waspurified by flash column chromatography (SP1, 12 g SiO₂ cartridge 100%DCM up to 95% DCM: 5% MeOH gradient) to give the title compound as ayellow solid (38 mg, 42% yield). LCMS method: 1, RT:5.26 min, MI 443.35[M+H]; NMR: (1H, 300 MHz, d6-dmso); 9.30 (1H, s), 8.79 (1H, s), 8.31(1H, s), 8.28 (1H, d), 7.89 (1H, s), 7.74 (2H, d), 7.65 (1H, d), 7.27(2H, t), 6.88 (1H, t), 4.52 (1H, t), 4.30 (2H, d, br), 4.07 (3H, s),3.16 (1H, d), 3.11 (2H, t, br), 1.83 (2H, d, br), 1.72 (1H, s, br), 1.33(2H, q, br), 1.13 (2H, dd)

Synthesis of2-{3-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-R-pyrrolidin-1-yl}-acetamide[245]

To a mixture of[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine[238](50mg, 0.121 mmol) and K₂CO₃ (50 mg, 0.363 mmol) in DMF (1 mL) was added2-bromoacetamide (17 mg, 0.121 mmol). The reaction mixture was heated at80° C. for 4 hr. Water (10 mL) was added and the reaction mixture wasextracted with EtOAc (2×10 mL), the extracts were combined and washedwith brine (20 mL), dried (MgSO₄) filtered and evaporated under reducedpressure to give a pale yellow oil, which was diluted with MeOH (5 mL)and poured onto a 1 g SCX-2 cartridge and washed with MeOH beforeeluting with 2N NH3/MeOH which was evaporated. The resulting oil wastriturated in Et₂O to give the title compound as a white solid (12 mg,17% yield). LCMS method: 1, RT:2.17 min, MI 471 [M+H];

NMR: (1H, 300 MHz, d6-dmso); 9.32 (1H, s), 8.78 (1H, s), 8.35 (1H, s),8.31 (1H, d), 8.23 (1H, d), 7.76 (2H, d), 7.70 (1H, d), 7.28 (2H, t),7.13 (1H, s), 6.90 (1H, t), 4.82 (1H, s), 4.15 (3H, s), 3.10 (2H, d),3.00 (1H, m), 2.89 (1H, m), 2.81 (1H, m), 2.57 (1H, m), 2.40 (1H, m),1.88 (1H, m).

General synthesis of 5-chloro substituted 2-amino pyridyl substituted2-(2-amino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl amine derivativesof general formula [G-008] Scheme B2

5-chloro 2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl aminederivatives of general formula [G-007] were prepared by the reaction ofa 5-chloro 2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-olderivative of general formula [G-006] with2,4,6-triisopropylbenzenesulfonyl chloride in a polar aprotic solventsuch as DMA, DMF, NMP with a tertiary alkylamine base such as Et₃N,DIPEA or NMM and a catalytic amount of DMAP. The intermediate6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl ester wasthen reacted with a primary or secondary amino derivative, of generalformula [G-004], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. 5-chloro2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl amine derivativesof general formula [G-007] was involved in a Buchwald type reactionutilising a suitable amine, of general formula [G-005], a palladiumcatalyst such as Pd(dba)₂ or Pd(OAc)₂, a ligand such as Xantphos and abase such as NaOtBu or Cs₂CO₃ in a polar solvent such as dioxane or acombination of dioxane and DMA at high temperature either by heatingthermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the intermediate was purified by columnchromatography and the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, HCl in a solvent such as DCM,DCE or 1,4-dioxane or by catch and release sulfonic acidic resins suchas polymer supported toluene sulfonic acid and the crude reactionproduct was purified by normal phase chromatography or reverse phasepreparative HPLC.

Synthesis of[4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine[246]

3,5-Dichloro-N-[(2-chloro-pyridin-4-yl)-imino-methyl]-isonicotinamide[B007]

A mixture of 3,5-dichloropyridine-4-carboxylic acid (15 g, 78.12 mmol),DIPEA (37.5 mL, 214 mmol) in DMF (400 mL) was stirred at roomtemperature then HATU (29.7 g, 78.12 mmol) was added in one portion andthe mixture was left to stir for 45 min. 2-Chloro-isonicotinamide (14.25g, 74.2 mmol) was added and the mixture left to stir for a further 2hours. The crude reaction mixture was then poured onto water (800 mL)and left to stir overnight. The crude reaction mixture was filtered andthe solid washed with water, then dried in in a vacuum oven over nightto give the title compound (22 g, 85% yield) as an off white solid: LCMSmethod: 1, RT:4.89 min, MI 330 [M+H]; NMR: (1H, 300 MHz, d6-dmso); 10.25(1H, br s), 10.10 (1H, br s), 8.70 (2H, s), 8.57 (1H, s), 7.99 (1H, s),7.88 (1H, s).

5-Chloro-2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol [B008]

3,5-Dichloro-N-[(2-chloro-pyridin-4-yl)-imino-methyl]-isonicotinamide[B007](10 g, 30.34 mmol) cesium carbonate (19.8 g, 60.69 mmol) and DMA(180 mL) were stirred at room temperature. The mixture was flushed withnitrogen then iron(III) chloride (0.98 g, 6.07 mmol) was added and themixture heated at 140 C overnight under an atmosphere of nitrogen. Thecrude reaction mixture was cooled then poured onto a mixture of icewater, the mixture was then acidified by the addition of glacial aceticacid, and the mixture was then left to stir at room temperature for 2hours. The solid precipitate was collected by filtration, washed withwater then dried in a vacuum oven over night to give the title compound(5.26 g, 59% yield) as a pale brown solid: LCMS method: 1, RT:4.83 min,MI 293 [M+H];

4-[5-Chloro-2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B009]

A mixture of5-Chloro-2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol[B008](1.05 g, 3.58 mmol), anhydrous DMF (40 mL), triethylamine (1.5 mL,10.7 mmol) and DMAP (440 mg, 3.58 mmol) was sonicated for 45 min.2,4,6-Triisopropyl-benzenesulfonyl chloride (1.3 g, 4.3 mmol) was addedand the reaction mixture left to stir at room temperature for 2 hr.During this time the material went into solution to form a viscoussolution. 1-Boc-piperazine (0.800 g, 4.3 mmol) was added and thereaction mixture was left to stir at room temperature overnight. Thesolvent was evaporated under reduced pressure and residue triturated inDCM to give brown solid, which was purified by flash columnchromatography (SP1, 20 g SiO₂ cartridge 100% DCM up to 95% DCM: 5% MeOHgradient) to give the title compound [B009] as a beige solid (1.1 g, 67%yield). LCMS method: 1, RT:5.50 min, MI: 461 [M+H]; NMR: (1H, 300 MHz,d6-dmso); 9.20 (1H, s), 8.67 (1H, s), 8.62 (1H, d), 8.33 (1H, d), 8.32(1H, s), 7.94 (1H, s), 3.72 (4H, m, br), 3.53 (4H, m, br), 1.41 (9H, s).

4-[5-Chloro-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B010]

A mixture of4-[5-Chloro-2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B009](0.150 g, 0.325 mmol), Aniline (61 μL, 0.650mml), Pd(OAc)₂ (4 mg, 0.017 mmol), Xantphos (19 mg, 0.033 mmol), cesiumcarbonate (212 mg, 0.650 mmol) and anhydrous dioxane (1 ml) was heatedat 900 overnight. Solvent evaporated under reduced pressure and residuepurified by flash column chromatography (SP1, 20 g SiO₂ cartridge 100%DCM up to 97% DCM: 3% MeOH gradient) to give the title compound [B010]as a beige solid (65 mg, 39% yield). LCMS method: 1, RT:4.34 min, MI:518.31 [M+H].

[4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine[246]

A mixture of4-[5-Chloro-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B010](60 mg, 0.125 mmol) in 4N HCl in dioxane (1mL) was stirred at room temperature for 2 hours. After completionsolvent was evaporated in vacuo and residue diluted with MeOH (5 mL) andpoured onto a 1 g SCX-2 cartridge and washed with DCM and MeOH beforeeluting with 2N NH3/MeOH which was evaporated evaporated under reducedpressure. The residue purified by flash column chromatography (SP1, 20 gSiO₂ cartridge 100% DCM up to 90% DCM: 10% MeOH gradient) to give thetitle compound [246] as a yellow solid (23 mg, 44% yield). LCMS method:1, RT:5.48 min, MI: 418.29 [M+H]; NMR: (1H, 300 MHz, d6-dmso); 9.33 (1H,s), 9.12 (1H, s), 8.60 (1H, s), 8.32 (1H, d), 7.89 (1H, s), 7.74 (2H,d), 7.65 (1H, dd), 7.27 (2H, t), 6.89 (1H, t), 3.68 (4H, m), 3.15 (1H,d), 2.86 (4H, m).

The following compounds were synthesised according to the generalsynthesis shown in scheme [B2]

Analysis Ex Amine Aniline LCMS NMR Name 247

Method 5: RT: 3.18 min, MI: 436 [M + H] (1H, 500 MHz, d6-dmso) 8.99 (1H,s), 8.60 (1H, s), 8.29 (1H, d), 8.19 (1H, m), 8.02 (1H, d), 7.69 (1H,d), 7.22 (1H, m), 7.14 (1H, m), 7.00 (1H, m), 3.68 (4H, br s), 2.86 (4H,br s) [4-(5-Chloro-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- (2-fluoro- phenyl)-amine 248

Method 5: RT: 3.37 min, MI: 511 [M + H] (1H, 500 MHz, d6-dmso) 8.97 (1H,s), 8.74 (1H s), 8.41 (1H, s), 8.29 (1H, d), 8.22 (1H, t), 8.04 (1H, s),7.72 (1H, d), 7.31 (1H, m), 7.22 (1H, m), 7.14 (1H, m), 7.09 (2H, m), 7(1H, m), 3.54 (4H, s), 2.83 (4H, s). (2-Fluoro- phenyl)-{2-[2-(2-fluoro- phenylamino)- pyridin-4-yl]-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-5- yl}-amine 249

Method 5: RT: 2.58 min, MI: 444 [M + H] (1H, 500 MHz, d6-dmso) 10.51(1H, s), 9.25 (1H, s), 8.70 (1H, s), 8.65 (1H, s), 8.50 (2H, dd), 7.91(1H, d), 7.31 (1H, d), 3.91 (4H, br s), 3.33 (4H, br s) 4-{5-(4-Cyano-pyridin-2- ylamino)-2-[2- (4-cyano- pyridin-2- ylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4- yl}-piperazine 250

Method 5: RT: 2.80 min, MI: 432.15 [M + H] (1H, 500 MHz, d6-dmso) 9.33(1H, s), 9.12 (1H, s), 8.59 (1H, s), 8.31 (1H, d), 7.89 (1H, s), 7.73(2H, d), 7.64 (1H, d), 7.27 (2H, t), 6.90 (1H, t), 4.09 (2H, m, br),3.31 (2H, m, br), 3.16 (1H, d), 2.88 (2H, m, br), 1.01 (3H, s){4-[5-Chloro-4 ((S)-3-methyl- piperazin-1-yl) pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2- yl}-phenyl- amine 251

Method 5: RT: 2.64 min, MI: 384.08 [M + H] (1H, 500 MHz, d6-dmso) 10.64(1H, s), 9.20 (1H, s), 9.09 (1H, s), 8.64 (1H, s), 8.47 (1H, d), 8.00(1H, d), 3.77 (4H, m), 3.05 (4H, m), 2.13 (3H, s) N-[4-(5-Chloro-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2- yl)-pyridin-2-yl]-acetamide 252

Method 5: RT: 3.60 min, MI: 454 [M + H] (1H, 300 MHz, d6-dmso) 9.26 (1H,bs), 9.19 (1H, s), 8.66 (1H, s), 8.35 (1H, d), 8.09 (2H, m), 7.75 (1H,dd), 7.14 (1H, m), 7.04 (1H, m), 3.79 (4H, s), 3.08 (4H, s)[4-(5-Chloro-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- (2,3-difluoro- phenyl)-amine 253

Method 5: RT: 2.69 min, MI: 437 [M + H] (1H, 500 MHz, d6-dmso) 10.15(1H, s), 9.16 (1H, s), 8.69 (1H, s), 8.63 (1H, s), 8.38 (1H, s), 7.82(2H, s), 7.72 (1H, s), 6.58 (1H, s), 3.88 (4H, s), 3.25 (4H, s)[4-(5-Chloro-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- (6-fluoro- pyridin-2-yl)- amine 254

Method 5: RT: 2.17 min, MI: 454 [M + H] (1H, 300 MHz, d6-dmso) 9.24 (1H,s), 8.85 (1H, s), 8.71 (1H, s), 8.20 (1H, d), 7.82 (1H, s), 7.69 (1H,dd), 7.17 (2H, m), 3.87 (4H, s), 3.31 (4H, s) [4-(5-Chloro-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2- yl)-pyridin-2-yl]-(2,6-difluoro- phenyl)-amine 255

Method 5: RT: 3.29 min, MI: 454 [M + H] (1H, 300 MHz, d6-dmso) 9.15 (1H,s), 8.98 (1H, s), 8.62 (1H, s), 8.27 (1H, d), 8.20 (1H, s), 8.13 (1H,m), 7.97 (1H, s), 7.70 (1H, dd), 7.30 (1H, m), 7.06 (1H, m), 3.72 (4H,s), 2.93 (4H, s) [4-(5-Chloro-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2- yl)-pyridin-2-yl]- (2,4-difluoro- phenyl)-amine 256

Method 5: RT: 2.24 min, MI: 433 [M + H] (1H, 300 MHz, d6-dmso) 9.83 (1H,s), 9.16 (1H, s), 8.79 (1H, s), 8.61 (1H, s), 8.38 (1H, d), 8.13 (1H,d), 7.78 (1H, dd), 7.64 (1H, s), 6.76 (1H, d), 3.71 (4H, s), 2.88 (4H,s), 2.29 (3H, s) [4-(5-Chloro-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2- yl)-pyridin-2-yl]- (4-methyl- pyridin-2-yl)- amine 257

Method 5: RT: 3.42 min, MI: 472 [M + H] (1H, 500 MHz, d6-dmso) 9.19 (1H,s), 9.08 (1H, s), 8.65 (1H, s), 8.22 (1H, d), 7.88 (1H, s), 7.71 (1H,d), 7.35-7.29 (1H, m), 7.23- 7.14 (1H, m), 3.79 (4H, s), 3.12 (4H, s).[4-(5-Chloro-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- (2,3,6-trifluoro- phenyl)-amine 258

Method 5: RT: 5.38 min, MI: 437 [M + H] (1H, 500 MHz, d6-dmso) 10.02(1H, s), 9.25 (1H, s), 8.72 (1H, s), 8.69 (1H, s), 8.41 (1H, d), 8.28(1H, d), 7.93 (1H, dd), 7.82 (1H, dd), 7.69 (1H, m), 3.89 (4H, s), 3.27(4H, s) [4-(5-Chloro-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- (5-fluoro- pyridin-2-yl)- amine 259

Method 5: RT: 5.92 min, MI: 487 [M + H] (1H, 500 MHz, d6-dmso) 10.40(1H, s), 9.21 (1H, s), 8.72 (1H, s), 8.66 (1H, s), 8.52 (1H, d), 8.47(1H, d), 8.32 (1H, s), 7.88 (1H, d), 7.23 (1H, d), 3.81 (4H, s), 3.07(4H, s) [4-(5-Chloro-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- (4- trifluoromethyl- pyridin-2-yl)- amine 260

Method 5: RT: 5.32 min, MI: 444 [M + H] (1H, 500 MHz, d6-dmso) 10.25(1H, s), 9.19 (1H, s), 8.94 (1H, s), 8.66 (1H, s), 8.58 (1H, dd), 8.48(1H, d), 8.03 (1H, s), 7.93 (1H, d), 7.89 (1H, d), 3.80 (4H, s), 3.08(4H, s) 5-[4-(5-Chloro- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2- ylamino]- pyridine-2- carbonitrile 261

Method 5: RT: 5.27 min, MI: 583 [M + H] (1H, 500 MHz, d6-dmso) 9.05 (1H,s), 8.74 (1H, s), 8.37 (1H, s), 8.23 (1H, s), 8.21 (1H, s), 7.88 (1H,s), 7.72 (1H, dd), 7.37-7.17 (4H, m), 3.62 (4H, s), 2.88 (4H, s){4-Piperazin-1- yl-2-[2-(2,3,6- trifluoro- phenylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-5- yl}-(2,3,6- trifluoro- phenyl)-amine 262

Method 5: RT: 3.37 min, MI: 511 [M + H] (1H, 500 MHz, d6-dmso) 8.97 (1H,s), 8.74 (1H, s), 8.41 (1H, s), 8.29 (1H, d), 8.22 (1H, t), 8.04 (1H,s), 7.72 (1H, d), 7.31 (1H, m), 7.22 (1H, m), 7.14 (1H, m), 7.09 (2H,m), 7 (1H, m), 3.54 (4H, m), 2.83 (4H, s) (2,6-Difluoro- phenyl)-{2-[2-(2,6-difluoro- phenylamino)- pyridin-4-yl]-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin-5- yl}-amine

General synthesis of substituted 2-amino pyridyl substituted2-(2-amino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl amine derivativesof general formula [G-003] Scheme B3

5-chloro 2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl aminederivatives of general formula [G-007] were prepared by the reaction ofa 5-chloro 2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-olderivative of general formula [G-006] with2,4,6-triisopropylbenzenesulfonyl chloride in a polar aprotic solventsuch as DMA, DMF, NMP with a tertiary alkylamine base such as Et₃N,DIPEA or NMM and a catalytic amount of DMAP. The intermediate6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl ester wasthen reacted with a primary or secondary amino derivative, of generalformula [G-004], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. 5-chloro2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl amine derivativesof general formula [G-007] was involved in a Buchwald type reactionutilising a suitable amine, of general formula [G-005], a palladiumcatalyst such as Pd(dba)₂ or Pd(OAc)₂, a ligand such as Xantphos and abase such as NaOtBu or Cs₂CO₃ in a polar solvent such as dioxane or acombination of dioxane and DMA at high temperature either by heatingthermally or using a microwave reactor. The 5-chlotro 2-amino-pyridylsubstituted 2-(2-amino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl aminederivatives of general formula [G-008]. were reacted in a Suzuki typereaction utilising a suitable boronic acid or boronic ester, of generalformula [G-009], a palladium catalyst such as Pd(PPh₃)₄ or Pd(PPh₃)₂Cl₂a base such as Et₃N, KOH, Na₂CO₃ or NaOH in a polar solvent such asEtOH, THF, DMA or dioxane at high temperature either by heatingthermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the intermediate was purified by columnchromatography and the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, HCl in a solvent such as DCM,DCE or 1,4-dioxane or by catch and release sulfonic acidic resins suchas polymer supported toluene sulfonic acid and the crude reactionproduct was purified by normal phase chromatography or reverse phasepreparative HPLC.

Synthesis of[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-phenyl)-amine[263]

4-{5-Chloro-2-[2-(2-fluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperazine-1-carboxylicacid tert-butyl ester [B010]

A mixture of4-[5-Chloro-2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B009](3 g, 6.48 mmol), 2-fluoroaniline (654 μL,6.48 mml), Pd(OAc)₂ (79 mg, 0.324 mmol), Xantphos (375 mg, 0.648 mmol),ceasium carbonate (4.11 g, 12.6 mmol) and anhydrous dioxane (20 ml) washeated at 900 overnight. Solvent was evaporated under reduced pressureand residue purified by flash column chromatography (ISCO, 120 g SiO₂cartridge 100% cyclohexane up to 70% cyclohexane: 30% Ethylacetategradient) to give the title compound [B010] as a yellow solid (1.2 g,52% yield). LCMS method: 5, RT:4.19 min, MI 516.57 [M+H].

4-{5-Cyclopropyl-2-[2-(2-fluoro-phenylamino)-pyridin-4y-yl]pyrido[3,4-d]pyrimidin-4-yl}-piperazine-1-carboxylicacid tert-butyl ester [B011]

A mixture of4-{5-Chloro-2-[2-(2-fluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperazine-1-carboxylicacid tert-butyl ester [B010](1.8 g, 3.36 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (137mg, 0.168 mmol), K₃PO₄ (2.14 g, 10.075 mmol), cyclopropyl boronic acid(578 mg, 6.72 mmol) and anhydrous dioxane (30 ml) plus few drops of DMAwas added to a microwave vial. Solvent was evaporated under reducedpressure and residue purified by flash column chromatography (ISCO, 40 gSiO₂ cartridge 100% cyclohexane up to 70% cyclohexane: 30% Ethylacetategradient) to give the title compound [B011] as a yellow solid (950 mg,52% yield). LCMS method: 5, RT:4.72 min, MI 542 [M+H].

[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-phenyl)-amine[263]

A mixture of4-{5-Cyclopropyl-2-[2-(2-fluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperazine-1-carboxylicacid tert-butyl ester [B011](300 mg, 0.554 mmol) in 4N HCl in dioxane(1.5 mL) was stirred at room temperature for 2 hours. Solvent wasevaporated under reduced pressure and residue purified by reverse phaseflash column chromatography (ISCO, 24 g SiO₂ cartridge, 100% H₂O:0.1%formic acid up to 20% H₂O:0.1% formic acid: 80% MeOH: 0.1% formic acidgradient) The residue was diluted with MeOH (5 mL) and poured onto a 1 gSCX-2 cartridge and washed with DCM and MeOH before eluting with 2NNH3/MeOH which was evaporated under reduced pressure to give the titlecompound [263] as a yellow solid (110 mg, 45% yield). LCMS method: 1,RT:4.03 min, MI 442 [M+H]; NMR: (1H, 500 MHz, d6-dmso); 8.95 (1H, s),8.27 (1H, d), 8.21 (1H, m), 8.08 (1H, s), 8.03 (1H, s), 7.70-7.69 (1H,dd), 7.23 (1H, m), 7.14 (1H, m), 6.99 (1H, m), 3.78-3.62 (4H, m), 2.84(4H, s), 2.61 (1H, m), 1.25-1.24 (2H, m), 1.02-1.01 (2H, m).

The following compounds were synthesised according to the generalsynthesis shown in scheme [B3]

Analysis Ex Amine Aniline LCMS NMR Name 264

Method 5: RT: 3.01 min, MI: 460 [M + H] (1H, 500 MHz, d6-dmso) 8.95 (1H,s), 8.14 (1H, d), 8.08 (1H, s), 7.79 (1H, s), 7.64 (1H, d), 7.26 (1H,m), 7.15 (2H, m), 3.68 (4H, br s), 2.83 (4H, s), 2.61 (1H, m), 1.23 (2H,m), 1.02 (2H, m) [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]-(2,6- difluoro-phenyl)-amine265

Method 5: RT: 2.62 min, MI: 450 [M + H] (1H, 500 MHz, d6-dmso) 10.39(1H, s), 9.05 (1H, s), 8.36 (1H, s), 8.48 (2H, dd), 8.35 (1H, s), 7.91(1H, d), 7.31 (1H, d), 3.91 (4H, s), 3.33 (4H, s), 2.67 (1H, s),1.24-1.26 (2H, m), 1.07-1.09 (2H, m). 2-[4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2- ylamino]-isonicotinonitrile 266

Method 5: RT: 2.60 min, MI: 478 [M + H] (1H, 500 MHz, d6-dmso) 9.04 (1H,s), 9.00 (1H, s), 8.21 (1H, d, 8.13 (1H, s), 7.88 (1H, s), 7.72 (1H,dd), 7.32 (1H, m), 7.20 (1H, m), 3.76 (4H, s), 3.02 (4H, s), 2.63 (1H,m), 1.25 (2 H, m), 1.05 (2H, m) [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]- (2,3,6-trifluoro-phenyl)-amine 267

Method 5: RT: 9.34 min, MI: 439 [M + H] (1H, 300 MHz, d6-dmso) 9.80 (1H,s), 8.99 (1H, s), 8.78 (1H, s), 8.38 (1H, d), 8.10 (2H, m), 7.79 (1H,d), 7.66 (1H, s), 6.74 (1H, d), 3.73 (4H, bs), 2.92 (4H, s), 2.63 (1H,m), 2.29 (3H, s), 1.27 (2H, m), 1.04 (2H, m) [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)- amine 268

Method 5: RT: 4.80 min, MI: 511 [M + H] (1H, 500 MHz, d6-dmso) 10.19(1H, s), 9.02 (1H, s), 8.72 (1H, s), 8.43 (1H, d), 7.86 (2H, m), 7.74(1H, d), 7.62-7.53 (1H, m), 6.60 (1H, dd), 4.05 (1H, m), 3.61 (2H, m),3.05 (4H, s), 2.63 (1H, t), 1.29 (2H, m), 1.08 (2H, m){4-[5-Cyclopropyl-4- (3-trifluoromethyl- piperazin-1-yl)-pyrido[3,4-d]pyrimidin- 2-yl]-pyridin-2-yl}-(6- fluoro-pyridin-2-yl)-amine 269

Method 5: RT: 3.21 min, MI: 493 [M + H] (1H, 500 MHz, d6-dmso) 10.39 (s,1H), 9.08 (s, 1H), 8.73 (s, 1H), 8.53 (d, 1H), 8.47 (d, 1H), 8.33 (s,1H), 8.19 (s, 1H), 7.90 (d, 1H), 7.23 (d, 1H), 3.93 (s, 4H), 3.32 (s,4H), 2.69 (m, 1H), 1.27 (m, 2H), 1.078 (m, 2H) [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]-(4-trifluoromethyl-pyridin- 2-yl)-amine 270

Method 5: RT: 5.71 min, MI: 493 [M + H] (1H, 500 MHz, d6-dmso) 10.11 (s,1H), 9.06 (s, 1H), 8.96 (d, 1H), 8.62 (dd, 1H), 8.46 (d, 1H), 8.18 (s,1H), 8.05 (s, 1H), 7.87 (dd, 1H), 7.82 (d, 1H), 3.85 (s, 4H), 3.28 (s,4H), 2.68 (m, 1H), 1.27 (m, 2H), 1.08 (m, 2H) [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin- 3-yl)-amine 271

Method 5: RT: 5.25 min, MI: 433 [M + H] (1H, 500 MHz, d6-dmso) 9.99 (1H,s), 9.07 (1H, s), 8.71 (1H, s), 8.40 (1H, d), 8.27 (1H, d), 8.18 (1H,s), 7.94 (1H, dd), 7.83 (1H, dd), 7.68 (1H, m), 3.93 (4H, s), 3.27 (4H,s), 2.70 (1H, m), 1.26 (2H, m), 1.07 (2H, m) [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]-(5-fluoro-pyridin-2-yl)- amine

General synthesis of 5-cyclopropyl substituted 2-amino pyridylsubstituted 2-(2-amino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl aminederivatives of general formula [G-012]

5-cyclopropyl 2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamine derivatives of general formula [G-011] were prepared by thereaction of a 5-cyclopropylo2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol derivative ofgeneral formula [G-010] with 2,4,6-triisopropylbenzenesulfonyl chloridein a polar aprotic solvent such as DMA, DMF, NMP with a tertiaryalkylamine base such as Et₃N, DIPEA or NMM and a catalytic amount ofDMAP. The intermediate6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl ester wasthen reacted with a primary or secondary amino derivative, of generalformula [G-004], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. 5-cyclopropyl2-(2-chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl amine derivativesof general formula [G-011] was involved in a Buchwald type reactionutilising a suitable amine, of general formula [G-005], a palladiumcatalyst such as Pd(dba)₂ or Pd(OAc)₂, a ligand such as Xantphos and abase such as NaOtBu or Cs₂CO₃ in a polar solvent such as dioxane or acombination of dioxane and DMA at high temperature either by heatingthermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the intermediate was purified by columnchromatography and the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, HCl in a solvent such as DCM,DCE or 1,4-dioxane or by catch and release sulfonic acidic resins suchas polymer supported toluene sulfonic acid and the crude reactionproduct was purified by normal phase chromatography or reverse phasepreparative HPLC.

Synthesis of[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4,5-dimethyl-oxazol-2-yl)-amine[272]

Synthesis of 3-Bromo-5-fluoro-isonicotinic acid tert-butyl ester [B012]

To a solution of LDA (2M, 72 mL, 144 mmol) in THF (100 mL) cooled toapproximately −70° C. was added dropwise via cannula a solution of3-bromo-5-fluoropyridine (21.12 g, 120 mmol) in anhydrous THF (50 mL)pre-cooled to −70° C. The rate of addition was controlled such that theinternal temperature did not rise above −65° C. The dark red-brownsolution was stirred for 1 hour. Di-tert-butyldicarbonate (52.4 g, 240mmol) in THF (50 mL) was cooled to −10° C. in a methanol/ice bath thenadded dropwise via cannula to the dark red-brown solution. The mixturewas stirred for 2 hours then allowed to warm to room temperature andstirred for another 1 hour. Saturated aqueous ammonium chloride (100 mL)was added slowly and then water (200 mL) and EtOAc (200 mL) and themixture was vigorously stirred for 45 minutes. The mixture wastransferred to a separatory funnel and the layers were separated. Theaqueous layer was extracted with EtOAc (200 mL). The THF and EtOAclayers were combined, dried over magnesium sulfate, filtered andevaporated. The recovered dark red-brown oil was purified by columnchromatography (Cyclohexane/AcOEt: 1/0 to 97/3). Fractions containingdesired material were concentrated in vacuo to yield the title compound[B012] as a pale yellow oil (14 g, 85%). LCMS method: 1, RT:5.44 min,MI: 277 [M+H]; NMR: (1H, 300 MHz, d6-dmso); 8.56 (s, 1H), 8.43 (s, 1H),1.62 (s, 9H).

Synthesis of 3-Cyclopropyl-5-fluoro-isonicotinic acid tert-butyl ester[B013]

A solution containing 3-Bromo-5-fluoro-isonicotinic acid tert-butylester [B012](5.52 g, 20 mmol), potassium phosphate tribasic (12.74 g, 60mmol) and cyclopropyl boronic acid (2.58 g, 30 mmol), in anhydrousdioxane (100 mL) was subjected to vacuum/argon balloon (three times).Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.408 g, 0.5 mmol) was added and the reactionheated at 96° C. overnight under positive pressure of nitrogen. Themixture was cooled to room temperature and was filtered through a pad of200 g silica and washed with EtOAc (1 L). The filtrate was concentratedin vacuo and the crude was purified by column chromatography(Cyclohexane/AcOEt: 98:2 to 96:4). The combined fractions wereconcentrated under reduced pressure to yield the title compound [B013]as a colourless oil (3.42 g, 72%). LCMS method: 1, RT: 5.36 min, MI: 238[M+H].

Synthesis of 3-Cyclopropyl-5-fluoro-isonicotinic acid [B014]

In a microwave vial, 3-cyclopropyl-5-fluoro-isonicotinic acid tert-butylester [B013](1.186 g, 5 mmol) was dissolved in anhydrous methanol andthen heated in microwave at 140° C. for 1 hr. The reaction wasconcentrated in vacuo to give the title compound [B014] 0.84 g (92%) asa white crystalline solid. LCMS method: 1, RT:1.51 min, MI: 182 [M+H].

Synthesis of2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-ol[B015]

A mixture of 3-Cyclopropyl-5-fluoro-isonicotinic acid [B014](5 g, 27.6mmol) and HATU (10.5 g, 82.86 mmol) was stirred in DMF (35 mL) and DIPEA(14.5 mL, 82.86 mmol) was added. The mixture was left to stir at rt for1 hour then 2-Chloro-isonicotinamidine hydrochloride (5.3 g, 27.52 mmol)was added in one portion and the mixture was left to stir at rt for 18hours. The crude reaction mixture was poured onto water (180 mL) andleft to stir for stirred for 2 hours and then the beige solid wascollected by filtration, washed with water and dried in a vacuum oven togiveN-[(2-Chloro-pyridin-4-yl)-imino-methyl]-3-cyclopropyl-5-fluoro-isonicotinamide(6.60 g, 75% yield) which was used in the next step without furtherpurification: LCMS method: 1, RT:3.45 min, MI: 319 [M+H]; NMR: (1H, 300MHz, d6-dmso); 10.25 (s, br, 1H), 9.92 (s, br, 1H), 8.59 (d, 1H), 8.42(s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.92 (dd, 1H), 2.01 (m, 1H), 0.98(m, 2H), 0.85 (m, 2H).

A mixture ofN-[(2-Chloro-pyridin-4-yl)-imino-methyl]-3-cyclopropyl-5-fluoro-isonicotinamide(6.60 g, 20.70 mmol) and Cs2CO3 (6.7 g, 20.7 mmol) and DMA (90 mL) washeated at 90° C. overnight. The reaction mixture was poured intoice/water (100 ml), then acidified by the dropwise adition of glacialacetic acid and the mixture was left to stir at 0 OC for 1 hour. Thebeige precipitate was collected by filtration and washed with water thendried in a vacuum oven to give the title compound [B015](4.8 g, 78%yield). LCMS method: 1, RT: 3.90 min, MI: 299 [M+H]; NMR: (1H, 300 MHz,d6-dmso); 12.92 (s, 1H), 8.88 (s, 1H), 8.66 (d, 1H), 8.25 (dd, 2H), 8.16(dd, 1H), 3.39 (m, 1H), 1.11 (m, 2H), 0.94 (m, 2H).

4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B016]

A mixture of2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-ol[B015](280 mg, 0.937 mmol), anhydrous DMF (9 mL), triethylamine (0.390mL, 2.81 mmol) and DMAP (115 mg, 0.937 mmol) was sonicated for 10 minthen stirred at room temperature for 10 min.2,4,6-Triisopropyl-benzenesulfonyl chloride (340 mg, 1.12 mmol) wasadded and the mixture was sonicated for 5 min then left to stir at roomtemperature for 2 hours. During this time the material went intosolution to form a viscous solution. 1-Boc-piperazine (190 mg, 1.03mmol) was added and the reaction mixture was left to stir at roomtemperature overnight. Solvent was evaporated under reduced pressure andresidue purified by flash column chromatography (SP1, 20 g SiO₂cartridge 100% DCM up to 95% DCM: 5% MeOH gradient) to give the titlecompound [B016] as a yellow solid (276 mg, 63% yield). LCMS method: 5,RT:5.16 min, MI: 467 [M+H]; NMR: (1H, 500 MHz, d6-dmso); 9.02 (1H, s),8.61 (1H, dd), 8.34 (2H, m), 8.15 (1H, s), 3.68-3.83 (4H, very broad s),3.51 (4H, br s), 2.59 (1H, m), 1.24 (2H, m), 1.16 (2H, m).

4-{5-Cyclopropyl-2-[2-(4,5-dimethyl-oxazol-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperazine-1-carboxylicacid tert-butyl ester [B017]

A mixture of4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B016](280 mg, 0.591 mmol),4,5-dimethyl-oxazol-2-ylamine (132 mg, 1.18 mml), Pd(OAc)₂ (7 mg, 0.030mmol), Xantphos (35 mg, 0.060 mmol), ceasium carbonate (384 mg, 1.18mmol) and anhydrous dioxane (1.5 ml) was heated at 900 overnight.Solvent was evaporated under reduced pressure and residue purified byflash column chromatography (SP1, 20 g SiO₂ cartridge 100% DCM up to 96%DCM: 4% MeOH gradient) to give the title compound [B017] as a beigesolid (61 mg, 19% yield). LCMS method: 5, RT: 4.07 min, MI: 543 [M+H].

[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4,5-dimethyl-oxazol-2-yl)-amine[272]

A mixture of4-{5-Cyclopropyl-2-[2-(4,5-dimethyl-oxazol-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperazine-1-carboxylicacid tert-butyl ester [B017](60 mg, 0.112 mmol) in 4N HCl in dioxane (1mL) was stirred at room temperature for 2 hours. After completionsolvent was evaporated under reduced pressure and residue diluted withMeOH (5 mL) and poured onto a Ig SCX-2 cartridge and washed with DCM andMeOH before eluting with 2N NH3/MeOH which was evaporated under reducedpressure. The residue was then purified by flash column chromatography(SP1, 10 g SiO₂ cartridge 100% DCM up to 90% DCM: 10% MeOH gradient) togive the title compound [272] as a yellow solid (22 mg, 44% yield). LCMSmethod: 5, RT:2.70 min, MI: 443 [M+H]; NMR: (1H, 500 MHz, d6-dmso);10.61 (1H, s), 9.17 (1H, s), 9.05 (1H, s), 8.38 (1H, d), 8.16 (1H, s),7.87 (1H, d), 3.94 (1H, s, br), 3.26 (4H, m, br), 2.69 (2H, m), 2.19(3H, s), 2.04 (3H, s), 1.25-1.22 (3H, m), 1.06-1.05 (2H, m).

The following compounds were synthesised according to the generalsynthesis shown in scheme [B4]

Analysis Ex Amine Aniline LCMS NMR Name 273

Method 5: RT: 1.91 min, MI: 416.17 [M + H] (1H, 500MHz, d6-dmso) 8.98(1H, s), 8.93 (1H, s), 8.32 (1H, d), 8.13 (1H, s), 7.92 (1H, s), 7.71-7.67 (3H, m), 7.29 (2H, t), 6.93 (1H, t), 4.28 (1H, d), 4.16 (1H, d),3.28 (1H, t), 3.05 (1H, dd), 2.78 (1H, t), 2.63 (1H, m), 2.17 (1H, m),1.25 (2H, m), 1.02-0.95 (2H, m), 0.77 (1H, m), 0.43 (2H, dd), 0.29-0.25(2H, m) {4-[5- Cyclopropyl-4- ((S)-3- cyclopropyl- piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}- phenyl-amine 274

Method 5: RT: 4.93 min, MI: 457 [M + H] (1H, 500MHz, d6-dmso) 8.97 (1H,s), 8.95 (1H, s), 8.26 (1H, d), 8.20 (1H, t), 8.08 (1H, s), 8.04 (1H,s), 7.70 (1H, dd), 7.22 (1H, dd), 7.14 (1H, t), 7.00 (1H, m), 4.07 (2H,m, br), 3.78 (1H, m, br), 3.54-3.40 (2H, m, br), 3.15 (1H, d), 2.59 (1H,m, br), 1.86 (2H, d, br), 1.25 (2H, d, br), 1.02 (2H, m, br). 1-{5-Cyclopropyl-2-[2- (2-fluoro- phenylamino)- pyridin-4-yl]- pyrido[3,4-d]pyrimidin-4- yl}-piperidin-4-ol 275

Method 5: RT: 3.24 min, MI: 466 [M + H] (1H, 400MHz, d6-dmso 90° C.)8.98 (1H, s), 8.91 (1H, s), 8.31 (1H, d), 8.12 (1H, s), 7.92 (1H, s),7.71-7.68 (3H, m), 7.29 (2H, t), 6.93 (1H, t), 4.31 (1H, d), 4.20 (1H,d), 3.70 (1H, s, br), 3.29 (1H, t), 3.22 (2H, s), 3.05 (1H, dd), 2.81(1H, t), 2.68-1.63 (1H, m), 1.65 (1H, m), 1.27-1.25 (2H, m), 1.03 (1H,m), 0.96 (6H, dd) {4-[5- Cyclopropyl-4- ((S)-3-isopropyl-piperazin-1-yl)- pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-phenyl-amine 276

Method 5: RT: 2.48 min, MI: 482.25 [M + H] (1H, 400MHz, d6-dmso 90° C.)8.97 (1H, s), 8.53 (1H, s), 8.29 (1H, dd), 8.13 (1H, s), 8.07 (1H, td),7.95 (1H, s), 7.71 (1H, dd), 7.23 (1H, dd), 7.21- 7.14 (1H, m),7.07-7.04 (1H, m), 4.28 (1H, d), 4.14 (1H, d), 3.27 (1H, t), 3.22 (1H,s), 3.04 (1H, m), 2.77 (1H, t), 2.62 (1H, m), 2.16 (1H, t), 1.24 (1H,m), 1.02-0.95 (2H, m), 0.78 (1H, m), 0.42 (2H, dd), 0.29- 0.24 (2H, m){4-[5- Cyclopropyl-4- ((S)-3- cyclopropyl- piperazin-1-yl)- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(2- fluoro-phenyl)- amine 277

Method 5: RT: 3.20 min, MI: 483 [M + H] (1H, 400MHz, d6-dmso 90° C.)9.75 (1H, s), 8.99 (1H, s), 8.69 (1H, s), 8.41 (1H, d), 8.14 (1H, s),7.86 (1H, dd), 7.82 (1H, qd), 7.70 (1H, dd), 6.55 (1H, dd), 4.29 (1H,d), 4.20 (1H, d), 3.30 (1H, t), 3.09-3.05 (1H, m), 2.80 (1H, t),2.68-2.63 (1H, m), 2.16 (1H, t), 1.26-1.24 (2H, m), 1.03-0.95 (2H, m),0.81-0.75 (1H, m), 0.42- 0.40 (2H, m), 0.28-0.24 (2H, m) {4-[5-Cyclopropyl-4- ((S)-3- cyclopropyl- piperazin-1-yl)- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(6- fluoro-pyridin-2- yl)-amine 278

Method 5: RT: 5.65 min, MI: 488 [M + H] (1H, 500MHz, d6-dmso) 9.52 (1H,s, br), 9.18 (1H, s, br), 8.51 (1H, s), 8.30 (1H, s), 8.09 (1H, s), 7.94(2H, d, br), 7.86 (1H, s), 7.46 (2H, m, br), 7.09 (1H, t, br), 4.27 (2H,m, br), 3.34 (2H, m, br), 3.09 (2H, m, br), 2.82 (1H, m, br), 1.88- 1.81(3H, m, br), 1.48 (1H, s, br), 1.38 (3H, m, br), 1.24-1.19 (2H, m, br)(4-{5- Cyclopropyl-4-[3- (1,1-difluoro- ethyl)-piperazin-1-yl]-pyrido[3,4- d]pyrimidin-2- yl}-pyridin-2-yl)- phenyl-amine 279

Method 5: RT: 5.48 min, MI: 424 [M + H] (1H, 500MHz, d6-dmso) 9.10 (1H,s), 8.35 (1H, d), 8.04 (1h, s), 8.00 (1H, s), 7.79 (1H, d), 7.44 (2H,d), 7.36 (2H, t), 7.06 (1H, t), 6.77 (1H, s), 3.76 (4H, m, br), 3.01(4H, m), 2.68 (1H, m), 1.26 (2H, m), 0.99 (2H, m) [4-(5- Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-phenyl-amine 280

Method 5: RT: 3.26 min, MI: 463 [M + H] (1H, 500MHz, d6-dmso) 9.28 (1H,s), 8.98 (1H, s), 8.31 (1H, d), 8.11 (1H, s), 7.91 (1H, s), 7.75 (2H,d), 7.69 (1H, d), 7.27 (1H, t), 6.89 (1H, t), 4.12 (2H, m, br), 3.20(1H, m, br), 2.94 (3H, m, br), 2.71 (4H, m, br), 1.25 (2H, m, br), 1.03(2H, m, br) {(S)-4-[5- Cyclopropyl-2-(2- phenylamino- pyridin-4-yl)-pyrido[3,4- d]pyrimidin-4-yl]- piperazin-2-yl}- acetonitrile

Synthesis ofCyclopentyl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine[281]

4-[2-(2-Cyclopentylamino-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B018]

A mixture of4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B016][prepared according to the general synthesisshown in Scheme B4](170 mg, 0.364 mmol), cyclopentylamine (73 L, 0.728mmol), Pd(t-Bu₃P)₂ (38 mg, 0.073 mmol), sodium tert-butoxide (54 mg,0.546 mmol) and anhydrous dioxane (2 ml) was heated at 110° C.overnight. Solvent was evaporated under reduced pressure and residuepurified by flash column chromatography (SP1, 20 g SiO₂ cartridge 100%DCM up to 96% DCM: 4% MeOH gradient) to give the title compound [B018]as a yellow solid (92 mg, 48% yield). LCMS: method: 5, RT: 4.19 min, MI516.57 [M+H].

Cyclopentyl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine[281]

A mixture of4-[2-(2-Cyclopentylamino-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [B018](90 mg, 0.178 mmol) in 4N HCl in dioxane (2mL) was stirred at room temperature for 2 hours. Solvent was evaporatedunder reduced pressure and residue diluted with MeOH (5 mL) and pouredonto a 1 g SCX-2 cartridge and washed with DCM and MeOH before elutingwith 2N NH3/MeOH which was evaporated under reduced pressure. Theresidue was then purified by flash column chromatography (SP1, 10 g SiO₂cartridge 100% DCM up to 95% DCM: 5% MeOH gradient) to give the titlecompound [281] as a yellow solid to give the title compound as a yellowsolid (26 mg, 37% yield). LCMS: method: 5, RT:2.22 min, MI 416.25 [M+H];NMR: (1H, 500 MHz, d6-dmso); 8.95 (1H, s), 8.10 (2H, d), 8.08 (1H, s),7.51 (1H, s), 7.38 (1H, dd), 6.75 (1H, d), 4.17 (1H, m), 3.84-3.65 (4H,m), 3.11 (4H, m), 2.91 (1H, m), 2.62 (2H, m), 1.98-1.92 (2H, m), 1.69(2H, m), 1.55 (2H, m), 1.46 (2H, m), 1.24-1.22 (2H, m), 1.03 (2H, m).

The following compounds were synthesised according to the generalsynthesis shown in scheme [B4]

Analysis Ex Amine 1 Amine 2 LCMS NMR Name 282

Method 5: RT: 2.43 min, MI: 430.28 [M + H] (1H, 500MHz, d6-dmso) 8.93(1H, s), 8.07 (1H, d), 8.06 (1H, s), 7.50 (1H, s), 7.35 (1H, dd), 6.63(1H, d), 3.76-3.58 (4H, m, br), 2.87 (4H, m, br), 2.67 (2H, m), 1.94(2H, d, br), 1.72 (2H, dt, br), 1.59 (1H, d, br), 1.37-1.17 (7H, m),1.02 (2H, m) Cyclohexyl-[4- (5-cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2- yl)-pyridin-2- yl]-amine 283

Method 5: RT: 1.93 min, MI: 432.23 [M + H] (1H, 500MHz, d6-dmso) 8.94(1H, s), 8.10 (1H, d), 8.07 (1H, s), 7.53 (1H, s), 7.40 (1H, d), 6.77(1H, d), 4.09-3.97 (2H, m), 3.88-3.86 (2H, m), 3.75-3.57 (4H, m), 3.41(2H, t), 3.15 (1H, d), 2.93 (4H, m), 2.62 (1H, m), 1.90 (2H, d, br),1.48-1.40 (2H, m), 1.28-1.23 (2H, m), 1.03 (2H, m) [4-(5- Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2- yl)-pyridin-2-yl]-(tetrahydro- pyran-4-yl)- amine 284

Method 5: RT: 3.75 min, MI: 484.21 [M + H] (1H, 400MHz, d4-MeOH 50° C.)9.01 (1H, s), 8.09 (1H, s), 8.07 (1H, d), 7.59 (1H, s), 7.54 (1H, dd),4.16-4.07 (1H, m), 3.71-3.66 (1H, m), 3.13-3.07 (1H, m), 2.75-2.68 (1H,m), 2.13-2.05 (2H, m), 1.82-1.76 (2H, m), 1.69-1.65 (2H, m), 1.60-1.52(2H, m), 1.28-1.23 (3H, m), 1.06-0.96 (2H, m) Cyclopentyl-{4-[5-cyclopropyl- 4-(3- trifluoromethyl- piperazin-1-yl)- pyrido[3,4-d]pyrimidin-2- yl]-pyridin-2- yl]-amine 285

Method 5: RT: 3.05 min, MI: 482.25 [M + H] (1H, 500MHz, d6-dmso) 8.92(1H, s), 8.05 (2H, m), 7.55 (1H, s), 7.33 (1H, d), 6.36 (1H, s), 3.80-3.52 (4H, m), 2.85 (4H, m, br), 2.62- 2.60 (1H, m), 2.10 (6H, m, br),2.05 (3H, m, br), 1.66 (6H, m, br), 1.24- 1.23 (2H, m, br), 1.18-1.16(1H, m), 1.10-1.08 (1H, m), 1.03-1.00 (2H, m) Adamantan-1- yl-[4-(5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2- yl)-pyridin-2-yl]-amine

Example 3032-Amino-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-benzamide

303a) 2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol was preparedfrom 2-Chloro-isonicotinonitrile (0.60 g, 4.3 mmol) and3-Amino-isonicotinic acid (0.50 g, 3.6 mmol) in an analogous manner toExample 1a. Product isolated as a tan solid (0.479 g, 51%). ¹HNMR (400MHz, d6-DMSO, δ, ppm): 13.13 (br s, 1H), 9.19 (s, 1H), 8.74 (d, J=4.2Hz, 1H), 8.66 (d, J=5.1 Hz, 1H), 8.24 (s, 1H), 8.15 (d, J=5.1 Hz, 1H),8.02 (d, J=4.8 Hz, 1H). MS=259, 261 (MH)+. 303b)(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester was prepared from2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol (1.50 g, 5.80mmol) and (R)-3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester(1.1 mL, 6.6 mmol) in an analogous manner to [B016]. Product wasisolated as a yellow foam (2.15 g, 87%). ¹HNMR (400 MHz, d6-DMSO, δ,ppm): 9.22 (s, 1H), 8.76 (d, J=5.7 Hz, 1H), 8.69 (d, J=5.4 Hz, 1H), 8.61(d, J=4.6 Hz, 1H), 8.37-8.29 (m, 3H), 4.94 (br s, 1H), 3.88-3.71 (m,1H), 3.55-3.29 (m, 3H), 2.37-2.25 (m, 1H), 2.19-2.04 (m, 1H), 1.46-1.39(m, 9H). MS=427, 429 (MH)+.

303c) A tube was charged with(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol), 2-Amino-benzamide (35.0mg, 0.257 mmol), Palladium Acetate (5.0 mg, 0.022 mmol),4,5-Bis-(di-tert-butyl-phosphanyl)-9,9-dimethyl-9H-xanthene (12.0 mg,0.0241 mmol), Cesium Carbonate (115.0 mg, 0.3530 mmol) and 1,4-Dioxane(1 mL, 10 mmol) under an atmosphere of Nitrogen. The tube was carefullyevacuated and backflushed with nitrogen once. The tube was sealed andheated at 100° C. and stirred overnight. The mixture was cooled to roomtemperature, diluted with dichloromethane (10 mL), filtered through aplug of diatomaceous earth and evaporated to a dark resin. To theresidue was added Trifluoroacetic acid (0.5 mL) and dichloromethane (0.5mL). The mixture was stirred for 1 hour and the volatiles wereevaporated. The residue was purified via reverse phase chromatographyusing a Gilson apparatus (10%→0% Acetonitrile:Water w/TFA modifier).2-Amino-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-benzamideas the trifluoroacetic acid salt was isolated as a yellow lyophilate(0.009 g, 9%).

¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.28 (s, 1H), 9.15 (s, 1H), 8.88 (brs, 2H), 8.75-8.70 (m, 2H), 8.55 (d, J=5.1 Hz, 1H), 8.27 (d, J=5.4 Hz,1H), 8.13 (d, J=4.3 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.24 (t, J=8.4 Hz,1H), 6.80 (d, J=8.6 Hz, 1H), 6.60 (t, J=7.2 Hz, 1H), 4.93 (br s, 1H),3.80-3.70 (m, 1H), 3.52-3.35 (m, 3H), 2.53-2.40 (m, 2H), 2.32-2.24 (m,1H). MS=427 (MH)+.

Example 3044-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-benzamide

4-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-benzamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and 4-Amino-benzamide(35.0 mg, 0.257 mmol) in an analogous manner to Example 303c. Productwas isolated as the trifluoroacetic acid salt as a yellow lyophilate(0.008 g, 8%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.67 (s, 1H), 9.24 (s,1H), 8.87 (br s, 2H), 8.74-8.69 (m, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.26(d, J=5.7 Hz, 1H), 8.02 (s, 1H), 7.84-7.74 (m, 6H), 7.13 (br s, 1H),4.95 (br s, 1H), 3.80-3.30 (m, 3H), 2.52-2.38 (m, 2H), 2.31-2.22 (m,1H). MS=427 (MH)+.

Example 3054-Amino-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-benzamide

4-Amino-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-benzamidewas a byproduct from Example 304 isolated as the trifluoroacetic acidsalt as an orange-brown lyophilate (0.012 g, 12%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 10.41 (s, 1H), 9.28 (s, 1H), 9.23 (s, 1H), 8.87 (br s,2H), 8.75-8.70 (m, 2H), 8.54-8.50 (m, 1H), 8.27 (d, J=5.2 Hz, 1H), 8.10(d, J=4.8 Hz, 1H), 7.85 (d, J=8.1 Hz, 2H), 6.61 (d, J=7.7 Hz, 2H),4.95-4.88 (m, 1H), 3.82-3.30 (m, 3H), 2.55-2.40 (m, 2H), 2.33-2.25 (m,1H).MS=427 (MH)+.

Example 306{4-[(1S,4S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine

306a)(1S,4S)-5-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester was prepared from2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol (250.0 mg, 0.9665mmol) and (1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acidtert-butyl ester (215.0 mg, 1.084 mmol) in an analogous manner toExample 301b. Product isolated as a yellow resin (0.110 g, 26%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.22 (s, 1H), 8.62-8.55 (m, 2H), 8.37-8.32(m, 2H), 8.07-8.03 (m, 1H), 5.53 (d, J=18.5 Hz, 1H), 4.62 (d, J=18.5 Hz,1H), 4.33 (br s, 1H), 3.92 (br s, 1H), 3.62-3.44 (m, 2H), 2.08-2.00 (m,2H), 1.45-1.30 (m, 9H). MS=439, 441 (MH)+. 306b){4-[(1S,4S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-aminewas prepared from(1S,4S)-5-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (115.0 mg, 0.2620 mmol) and Aniline (27.0 L, 0.296mmol) in an analogous manner to Example 303c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.133 g, 128%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.49 (br s, 1H), 9.28 (s, 1H), 9.23 (br s,1H), 8.65 (d, J=5.4 Hz, 1H), 8.45 (br s, 1H), 8.33-8.29 (m, 1H), 8.03(d, J=5.6 Hz, 1H), 7.99 (s, 1H), 7.76-7.70 (m, 3H), 7.32 (t, J=7.4 Hz,2H), 7.00-6.93 (m, 1H), 5.49 (s, 1H), 4.62 (s, 1H), 4.44 (d, J=10.8 Hz,1H), 4.12 (d, J=11.1 Hz, 1H), 3.61-3.41 (m, 2H), 2.34 (d, J=10.4 Hz,1H), 2.07 (d, J=10.9 Hz, 1H). MS=396 (MH)+.

Example 307 Pyrazine-2-carboxylic acid{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-amide

Pyrazine-2-carboxylic acid{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-amidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and Pyrazine-2-carboxylicacid amide (32.0 mg, 0.260 mmol) in an analogous manner to Example 303c.Product isolated as the trifluoroacetic acid salt as a pale yellowlyophilate (0.099 g, 100%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.50 (s,1H), 9.40 (s, 1H), 9.34 (s, 1H), 9.30 (s, 1H), 9.02-8.86 (m, 4H), 8.77(d, J=4.4 Hz, 1H), 8.74 (d, J=5.4 Hz, 1H), 8.60 (d, J=5.0 Hz, 1H), 8.28(d, J=5.5 Hz, 1H), 8.21 (d, J=5.1 Hz, 1H), 4.98-4.90 (m, 1H), 3.84-3.74(m, 2H), 3.54-3.38 (m, 3H), 2.53-2.42 (m, 1H), 2.35-2.25 (m, 1H). MS=414(MH)+.

Example 3083-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-benzamide

3-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-benzamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and 3-Amino-benzamide(35.0 mg, 0.257 mmol) in an analogous manner to Example 303c. Productisolated as the bis-trifluoroacetic acid salt as yellow lyophilate(0.005 g, 5%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.49 (s, 1H), 9.24 (s,1H), 8.85 (br s, 1H), 8.72 (d, J=5.1 Hz, 1H), 8.70-8.67 (m, 1H), 8.36(d, J=5.4 Hz, 1H), 8.24 (d, J=5.0 Hz, 1H), 8.18 (s, 1H), 7.99 (s, 1H),7.95-7.88 (m, 2H), 7.77 (d, J=4.5 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 7.37(d, J=8.1 Hz, 1H), 7.34-7.29 (m, 1H), 4.99-4.91 (m, 1H), 3.76-3.69 (m,1H), 3.51-3.45 (m, 1H), 3.43-3.34 (m, 3H), 2.50-2.38 (m, 2H), 2.31-2.22(m, 1H). MS=427 (MH)+.

Example 3093-Amino-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-benzamide

3-Amino-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-benzamidewas a byproduct from Example 309 isolated as a free base as an off-whitesolid (0.007 g, 7%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.53 (s, 1H),9.21 (s, 2H), 8.66 (d, J=5.3 Hz, 1H), 8.54 (br s, 1H), 8.53 (d, J=4.5Hz, 1H), 8.35-8.30 (m, 1H), 8.12 (d, J=4.8 Hz, 1H), 7.24-7.19 (m, 2H),7.15 (t, J=7.5 Hz, 1H), 6.77 (d, J=7.7 Hz, 1H), 5.31 (s, 2H), 4.77 (brs, 1H), 3.24 (br s, 1H), 3.05-2.80 (m, 3H), 2.23 (br s, 1H), 1.90 (br s,1H).MS=427 (MH)+.

Example 3102-(4-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenoxy)-acetamide

310a) To a stirred suspension of 4-Nitrophenol (2.00 g, 14.4 mmol) andPotassium carbonate (3.0 g, 22 mmol) in Acetone (20 mL, 300 mmol) wasadded Ethyl bromoacetate (1.60 mL, 14.4 mmol). The mixture was heated at30° C. overnight. The mixture was cooled to room temperature, dilutedwith ether (50 mL) and filtered through a plug of diatomaceous earth andevaporated. (4-Nitro-phenoxy)-acetic acid ethyl ester was isolated as anoff-white solid (3.20 g, 99%). ¹HNMR (400 MHz, CDCl3, δ, ppm): 8.22 (d,J=7.8 Hz, 2H), 6.98 (d, J=7.8 Hz, 2H), 4.72 (s, 2H), 4.29 (q, J=7.1 Hz,2H), 1.31 (t, J=7.1 Hz, 3H). MS=226 (MH)+.

310b) A Paar bottle (500 mL) was charged with 10% Palladium on Carbon(50% Wet)(5:45:50, Palladium:carbon black:Water, 3.0 g, 1.4 mmol)followed by a solution of (4-Nitro-phenoxy)-acetic acid ethyl ester(3.20 g, 14.2 mmol) in 2:1 Ethyl acetate:Methanol(2:1, Ethylacetate:Methanol, 75 mL, 510 mmol). The mixture was degassed and chargedwith Hydrogen (50 psi). The mixture was shaken on a Paar apparatus untiladsorption of Hydrogen ceased. The mixture was degassed and backflushedwith nitrogen. The mixture was filtered through a plug of diatomaceousearth and evaporated. (4-Amino-phenoxy)-acetic acid ethyl ester wasisolated as a tan solid (2.65 g, 96%). ¹HNMR (400 MHz, CDCl3, δ, ppm):6.77 (d, J=7.9 Hz, 1H), 6.63 (d, J=7.8 Hz, 1H), 4.54 (s, 2H), 4.26 (q,J=7.1 Hz, 2H), 3.40 (br s, 2H), 1.29 (t, J=7.1 Hz, 3H). MS=196 (MH)+.

310c)(R)-3-{2-[2-(4-Ethoxycarbonylmethoxy-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-ylamino}-pyrrolidine-1-carboxylic acid tert-butyl esterwas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (200.0 mg, 0.4685 mmol) and(4-Amino-phenoxy)-acetic acid ethyl ester (100.0 mg, 0.5122 mmol) in ananalogous manner to Example 303c. The orange residue was suspended inMethanol (1 mL, 20 mmol) and Water (1 mL, 60 mmol) and Lithium hydroxidemonohydrate (25.0 mg, 0.596 mmol) was added. The mixture was stirred atroom temperature overnight. The volatiles were evaporated to yield anorange solid. The orange solid was suspended in 1,4-Dioxane (5 mL, 60mmol). Pyridine (0.1 mL, 1 mmol) was added followed byDi-tert-Butyldicarbonate (105.0 mg, 0.4811 mmol) and Ammonium Carbonate(70.0 mg, 0.728 mmol). The mixture was stirred at room temperature forovernight. The mixture was diluted with dichloromethane (25 mL) andfiltered through a plug of diatomaceous earth and the filtrate wasevaporated. The solid was dissolved in dichloromethane (1 mL) andtrifluoroacetic acid (0.5 mL) was added. The mixture was stirred for 1hour at room temperature then the volatiles were evaporated. The residuewas purified via reverse phase chromatography using a Gilson apparatus(5%-30% Acetonitrile:Water w/ 0.1% TFA modifier).2-(4-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenoxy)-acetamidewas isolated as the trifluoroacetic acid salt as an orange-yellowlyophilate (0.118 g, 55%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.62 (br s,1H), 9.24 (s, 1H), 8.98 (br s, 2H), 8.76 (d, J=4.5 Hz, 1H), 8.73 (d,J=5.3 Hz, 1H), 8.27 (d, J=5.6 Hz, 1H), 8.21 (d, J=5.3 Hz, 1H), 7.96 (s,1H), 7.74 (d, J=5.5 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.54 (s, 1H), 7.42(s, 1H), 6.99 (d, J=8.4 Hz, 2H), 4.96-4.86 (m, 1H), 4.43 (s, 2H),3.74-3.64 (m, 1H), 3.54-3.34 (m, 3H), 2.45-2.35 (m, 1H), 2.31-2.21 (m,1H). MS=457 (MH)+.

Example 3112-(3-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenoxy)-acetamide

311a) (3-Nitro-phenoxy)-acetic acid ethyl ester was prepared fromm-Nitrophenol (2.00 g, 14.4 mmol) and Ethyl bromoacetate (1.60 mL, 14.4mmol) in an analogous manner to Example 310a.

Product isolated as a yellow oil (3.20 g, 99%). ¹HNMR (400 MHz, CDCl3,δ, ppm): 7.88 (d, J=8.1 Hz, 1H), 7.73 (s, 1H), 7.46 (t, J=8.3 Hz, 1H),7.27 (d, J=8.5 Hz, 1H), 4.71 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 1.32 (t,J=7.1 Hz, 3H). LC/MS=248 (M+Na)+. 311b) (3-Amino-phenoxy)-acetic acidethyl ester was prepared from (3-Nitro-phenoxy)-acetic acid ethyl ester(3.20 g, 14.2 mmol) in an analogous manner to Example 310b. Productisolated as an orange oil (2.60 g, 94%). ¹HNMR (400 MHz, CDCl3, δ, ppm):7.05 (t, J=7.8 Hz, 1H), 6.35-6.26 (m, 3H), 4.57 (s, 2H), 4.27 (q, J=7.2Hz, 2H), 3.67 (br s, 2H), 1.30 (t, J=7.1 Hz, 3H). MS=196 (MH)+.

311c)2-(3-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenoxy)-acetamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (200.0 mg, 0.4685 mmol) and(3-Amino-phenoxy)-acetic acid ethyl ester (100.0 mg, 0.5122 mmol) in ananalogous manner to Example 310c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.011 g, 5%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.40 (br s, 1H), 9.23 (s, 1H), 8.85 (br s,2H), 8.72 (d, J=5.3 Hz, 1H), 8.69 D, J=5.1 Hz, 1H), 8.35 (d, J=4.8 Hz,1H), 8.26 (d, J=5.3 Hz, 1H), 7.98 (s, 1H), 7.75 (d, J=5.2 Hz, 1H), 7.55(s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.20 (t,J=7.9 Hz, 1H), 6.51 (d, J=8.3 Hz, 1H), 4.98-4.90 (m, 1H), 4.41 (s, 2H),3.76-3.70 (m, 1H), 3.52-3.33 (m, 3H), 2.45-2.38 (m, 1H), 2.30-2.23 (m,1H). MS=457 (MH)+.

Example 3132-(4-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamide

313a) To a stirred suspension of [A]4-Nitrophenylacetic Acid (1.0 g, 5.5mmol) and Pyridine (0.27 mL, 3.3 mmol) in 1,4-Dioxane (10 mL, 100 mmol)was added Di-tert-Butyldicarbonate (1.3 g, 6.1 mmol). The mixture wasstirred for 10 minutes at room temperature then Ammonium Carbonate (0.80g, 8.3 mmol) was added. The mixture was stirred at room temperatureovernight. The volatiles were evaporated to a leave an off-white solid.The solid was triturated with methanol, filtered and rinsed withmethanol. The methanolic filtrate was evaporated.2-(4-Nitro-phenyl)-acetamide was isolated as an off-white solid (0.65 g,65%). ¹HNMR (400 MHz, d6-DMSO, 6, ppm):8.18 (d, J=7.9 Hz, 2H), 7.59 (brs, 1H), 7.54 (d, J=7.9 Hz, 2H), 7.01 (br s, 1H), 3.55 (s, 2H). LC/MS=181(MH)+.

313b) 2-(4-Amino-phenyl)-acetamide was prepared from2-(4-Nitro-phenyl)-acetamide (0.65 g, 3.6 mmol) in an analogous mannerto Example 310b. Product isolated as a pale yellow solid (0.57 g, 99%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 7.25 (br s, 1H), 6.89 (d, J=8.1 Hz,2H), 6.74 (br s, 1H), 6.47 (d, J=8.2 Hz, 2H), 4.89 (br s, 2H), 3.14 (s,2H). MS=151 (MH)+. 313c).2-(4-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamidewas prepared from[A](R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (200.0 mg, 0.4685 mmol) and2-(4-Amino-phenyl)-acetamide (85.0 mg, 0.566 mmol) in an analogousmanner to Example 303c. Product isolated as the trifluoroacetic acidsalt as a yellow lyophilate (0.029 g, 14%).

¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.36 (br s, 1H), 9.23 (s, 1H), 8.85(br s, 2H), 8.72 (d, J=5.6 Hz, 1H), 8.70-8.67 (m, 1H), 8.30 (d, J=5.1Hz, 1H), 8.25 (d, J=5.5 Hz, 1H), 7.96 (s, 1H), 7.72 (d, J=5.2 Hz, 1H),7.63 (d, J=7.4 Hz, 2H), 7.42 (br s, 1H), 7.20 (d, J=8.3 Hz, 2H), 6.86(br s, 1H), 4.96-4.87 (m, 1H), 3.75-3.65 (m, 1H), 3.51-3.30 (m, 5H),2.46-2.36 (m, 1H), 2.31-2.21 (m, 1H). MS=441 (MH)+.

Example 3142-(4-Amino-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

2-(4-Amino-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[34-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas a byproduct from Example 313. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.018 g, 8%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 10.84 (s, 1H), 9.24 (s, 1H), 9.12 (s, 1H),8.94 (br s, 2H), 8.71 (d, J=5.5 Hz, 2H), 8.50 (d, J=5.2 Hz, 1H), 8.26(d, J=5.7 Hz, 1H), 8.09 (d, J=4.6 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.08(d, J=7.5 Hz, 2H), 4.95-4.87 (m, 1H), 3.77-3.65 (m, 3H), 3.51-3.33 (m,3H), 2.47-2.36 (m, 1H), 2.31-2.21 (m, 1H). MS=441 (MH)+.

Example 3162-(3-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamide

316a) 2-(3-Nitro-phenyl)-acetamide was prepared from(3-Nitro-phenyl)-acetic acid (1.0 g, 5.5 mmol) in an analogous manner toExample 13a. Product isolated as a crude off-white solid (1.2 g, 50%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.15 (s, 1H), 8.10 (d, J=8.2 Hz, 1H),7.71 (d, J=7.7 Hz, 1H), 7.63-7.54 (m, 2H), 7.01 (br s, 1H), 3.56 (s,2H). MS=181 (MH)+. 316b) 2-(3-Amino-phenyl)-acetamide was prepared from2-(3-Nitro-phenyl)-acetamide (1.2 g, 6.7 mmol) in an analogous manner toExample 10b. Product isolated as an off-white solid (1.0 g, 70%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 7.32 (br s, 1H), 6.90 (t, J=7.7 Hz, 1H),6.79 (br s, 1H), 6.46 (s, 1H), 6.42-6.37 (m, 2H), 4.97 (br s, 2H), 3.18(s, 2H). MS=151 (MH)+. 316c)2-(3-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (200.0 mg, 0.4685 mmol) and2-(3-Amino-phenyl)-acetamide (85.0 mg, 0.566 mmol) in an analogousmanner to Example 303c. Product isolated as the trifluoroacetic acidsalt as a yellow lyophilate (0.055 g, 26%). ¹HNMR (400 MHz, d6-DMSO, δ,ppm): 9.50 (br s, 1H), 9.24 (s, 1H), 8.91 (br s, 2H), 8.72 (d, J=5.5 Hz,1H), 8.31 (d, J=5.4 Hz, 1H), 8.26 (d, J=5.7 Hz, 1H), 7.99 (s, 1H), 7.75(d, J=5.4 HZ, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.54 (s, 1H), 7.48 (br s,1H), 7.25 (t, J=7.7 Hz, 1H), 6.93-6.86 (m, 2H), 4.97-4.87 (m, 1H),3.76-3.66 (m, 1H), 3.54-3.34 (m, 5H), 2.46-2.36 (m, 1H), 2.31-2.21 (m,1H). MS=441 (MH)+.

Example 3172-(3-Amino-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

2-(3-Amino-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[34-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas a byproduct from Example 16. Product isolated as the trifluoroaceticacid salt as a pale yellow lyophilate (0.047 g, 23%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 10.90 (s, 1H), 9.24 (s, 1H), 9.14 (s, 1H), 8.94 (br s,2H), 8.75-8.70 (m, 2H), 8.51 (d, J=5.1 Hz, 1H), 8.26 (d, J=5.5 Hz, 1H),8.10 (dd, J=5.1, 1.1 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.10-7.02 (m, 3H),6.94 (d, J=6.6 Hz, 1H), 6.40-4.00 (m, 3H), 3.76 (s, 2H), 3.75-3.65 (m,1H), 3.52-3.32 (m, 3H), 2.47-2.36 (m, 1H), 2.31-2.21 (m, 1H). MS=441(MH)+.

Example 318{2-[2-(5-Phenyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

2-[2-(5-Phenyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.176 mmol) and5-Phenyl-pyridin-2-ylamine (36.0 mg, 0.212 mmol) in an analogous mannerto Example 303c. Product isolated as the trifluoroacetic acid salt as ayellow lyophilate (0.098 g, 97%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.28(s, 1H), 8.92 (br s, 2H), 8.78-8.74 (m, 2H), 8.66-8.63 (m, 2H), 8.49 (d,J=5.8 Hz, 1H), 8.29 (d, J=5.2 Hz, 1H), 8.24-8.18 (m, 1H), 8.04-8.01 (m,1H), 7.80-7.71 (m, 3H), 7.55-7.49 (m, 2H), 7.44-7.39 (m, 1H), 5.00-4.92(m, 1H), 3.80-3.71 (m, 1H), 3.55-3.35 (m, 3H), 2.48-2.40 (m, 1H),2.34-2.25 (m, 1H). MS=461 (MH)+.

Example 319{2-[2-(6-Morpholin-4-yl-pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(6-Morpholin-4-yl-pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.176 mmol) and6-Morpholin-4-yl-pyridin-3-ylamine (39.0 mg, 0.218 mmol) in an analogousmanner to Example 303c. Product isolated as the trifluoroacetic acidsalt as an orange-brown lyophilate (0.082 g, 80%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 9.71 (br s, 1H), 9.24 (s, 1H), 9.01 (br s, 2H), 8.77(d, J=5.5 Hz, 1H), 8.73 (d, J=5.5 Hz, 1H), 8.62 (br s, 1H), 8.29-8.24(m, 2H), 8.01-7.95 (m, 2H), 7.78 (dd, J=5.5, 1.3 Hz, 1H), 7.15 (d, J=9.2Hz, 1H), 4.98-4.90 (m, 1H), 3.78-3.67 (m, 5H), 3.55-3.34 (m, 8H),2.46-2.36 (m, 1H), 2.31-2.21 (m, 1H). MS=470 (MH)+.

Example 320(2-{2-[6-(4-Methyl-piperazin-1-yl)-pyridin-3-ylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine

(2-{2-[6-(4-Methyl-piperazin-1-yl)-pyridin-3-ylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.176 mmol) and6-(4-Methyl-piperazin-1-yl)-pyridin-3-ylamine (41.0 mg, 0.213 mmol) inan analogous manner to Example 303c. Product isolated as thetrifluoroacetic acid salt as a brown lyophilate (0.094 g, 90%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.86 (br s, 1H), 9.45 (br s, 1H), 9.22 (s,1H), 9.04 (br s, 2H), 8.76 (d, J=5.4 Hz, 1H), 8.72 (d, J=5.6 Hz, 1H),8.51 (d, J=2.7 Hz, 1H), 8.27 (d, J=5.8 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H),8.02 (dd, J=9.0, 2.6 Hz, 1H), 7.93 (s, 1H), 7.73 (dd, J=5.4, 1.2 Hz,1H), 7.02 (d, J=9.2 Hz, 1H), 4.99-4.90 (m, 1H), 4.38-4.25 (m, 2H),3.78-3.68 (m, 1H), 3.59-3.34 (m, 5H), 3.18-3.02 (m, 4H), 2.87 (s, 3H),2.47-2.36 (m, 1H), 2.31-2.22 (m, 1H). MS=483 (MH)+.

Example 3212-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile

2-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrilewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.176 mmol) and2-Amino-isonicotinonitrile (25.0 mg, 0.210 mmol) in an analogous mannerto Example 303c. Product isolated as the trifluoroacetic acid salt as apale yellow lyophilate (0.012 g, 13%).

Example 322{2-[2-(4-Imidazol-1-ylmethyl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(4-Imidazol-1-ylmethyl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.176 mmol) and4-Imidazol-1-ylmethyl-phenylamine (37.0 mg, 0.214 mmol) in an analogousmanner to Example 303c. Product isolated as the trifluoroacetic acidsalt as a yellow lyophilate (0.097 g, 95%). ¹HNMR (400 MHz, d6-DMSO, δ,ppm): 9.56 (s, 1H), 9.24 (t, J=1.4 Hz, 1H), 9.22 (s, 1H), 9.06 (br s,2H), 8.77 (d, J=5.4 Hz, 1H), 8.71 (d, J=5.5 Hz, 1H), 8.33 (d, J=5.5 Hz,1H), 8.27 (d, J=5.8 Hz, 1H), 7.97 (s, 1H), 7.83-7.76 (m, 4H), 7.70 (t,J=1.7 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 5.36 (s, 2H), 5.01-4.92 (m, 1H),3.78-3.69 (m, 1H), 3.55-3.34 (m, 3H), 2.47-2.36 (m, 1H), 2.31-2.22 (m,1H).

MS=464 (MH)+.

Example 3232-(3-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenoxy)-acetamide

2-(3-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenoxy)-acetamidewas prepared fromR)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (150.0 mg, 0.3283 mmol) and(3-Amino-phenoxy)-acetic acid ethyl ester (75.0 mg, 0.384 mmol) in ananalogous manner to Example 303c and Example 10c and Example Ic. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.082g, 41%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.42 (s, 1H), 8.94 (br s,1H), 8.89-8.80 (m, 2H), 8.41 (s, 1H), 8.34 (d, J=5.2 Hz, 1H), 8.16 (d,J=6.2 Hz, 1H), 7.95 (s, 1H), 7.72 (dd, J=5.4, 1.3 Hz, 1H), 7.54 (t,J=2.1 Hz, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.30-7.25 (m, 1H), 7.20 (t,J=8.2 Hz, 1H), 6.51 (dd, J=7.8, 1.7 Hz, 1H), 5.05-4.95 (m, 1H), 4.41 (s,2H), 4.16 (m, 3H), 3.73-3.64 (m, 1H), 3.52-3.30 (m, 3H), 2.53-2.45 (m,1H), 2.27-2.16 (m, 1H). MS=487 (MH)+.

Example 3242-(3-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamide

2-(3-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (150.0 mg, 0.3283 mmol) and2-(3-Amino-phenyl)-acetamide (60.0 mg, 0.400 mmol) in an analogousmanner to Example 303c. Product isolated as the trifluoroacetic acidsalt as a yellow lyophilate (0.043 g, 22%). ¹HNMR (400 MHz, d6-DMSO, δ,ppm): 9.36 (s, 1H), 9.00-8.77 (m, 3H), 8.40 (s, 1H), 8.31 (d, J=5.4 Hz,1H), 8.15 (d, J=6.2 Hz, 1H), 7.94 (s, 1H), 7.72-7.65 (m, 2H), 7.56 (s,1H), 7.46 (s, 1H), 7.22 (t, J=7.7 Hz, 1H), 6.90-6.83 (m, 2H), 5.05-4.95(m, 1H), 4.16 (s, 3H), 3.73-3.63 (m, 1H), 3.50-3.23 (m, 5H), 2.55-2.45(m, 1H), 2.26-2.16 (m, 1H). MS=471 (MH)+.

Example 3252-(3-Amino-phenyl)-N-{4-[5-methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

2-(3-Amino-phenyl)-N-{4-[5-methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas a byproduct from Example 24. Product isolated as the trifluoroaceticacid salt as a yellow lyophilate (0.033 g, 17%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 10.84 (s, 1H), 9.11 (s, 1H), 9.00-8.78 (m, 3H), 8.50(d, J=5.5 Hz, 1H), 8.40 (s, 1H), 8.15 (d, J=5.9 Hz, 1H), 8.06 (dd,J=5.2, 1.4 Hz, 1H), 7.25-7.10 (m, 1H), 7.00-6.65 (m, 3H), 5.00-4.01 (m,1H), 4.15 (s, 3H), 3.80-3.28 (m, 8H), 2.55-2.45 (m, 1H), 2.26-2.16 (m,1H). MS=471 (MH)+

Example 3262-(4-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamide

2-(4-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (150.0 mg, 0.3283 mmol) and2-(4-Amino-phenyl)-acetamide (60.0 mg, 0.400 mmol) in an analogousmanner to Example 303c. Product isolated as the trifluoroacetic acidsalt as a yellow lyophilate (0.072 g, 37%). ¹HNMR (400 MHz, d6-DMSO, δ,ppm): 9.29 (s, 1H), 9.10-8.80 (m, 3H), 8.40 (s, 1H), 8.31 (d, J=5.3 Hz,1H), 8.15 (d, J=6.1 Hz, 1H), 7.92 (s, 1H), 7.68 (dd, J=5.3, 1.3 Hz, 1H),7.63 (d, J=8.5 Hz, 2H), 7.43-7.39 (m, 1H), 7.18 (d, J=8.5 Hz, 2H), 6.84(s, 1H), 5.05-4.95 (m, 1H), 4.16 (s, 3H), 3.72-3.63 (m, 1H), 3.50-3.20(m, 5H), 2.54-2.45 (m, 1H), 2.26-2.16 (m, 1H). MS=471 (MH)+.

Example 3272-(4-Amino-phenyl)-N-{4-[5-methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

2-(4-Amino-phenyl)-N-{4-[5-methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas a byproduct from Example 26. Product isolated as the trifluoroaceticacid salt was isolated as a yellow lyophilate (0.025 g, 13%). ¹HNMR (400MHz, d6-DMSO, δ, ppm): 10.81 (s, 1H), 9.09 (s, 1H), 9.02-8.83 (m, 3H),8.49 (dd, J=5.2, 0.70 Hz, 1H), 8.40 (s, 1H), 8.16 (d, J=6.0 Hz, 1H),8.05 (dd, J=5.2, 1.5 Hz, 1H), 7.28 (d, J=7.8 Hz, 2H), 7.00-6.93 (m, 2H),5.01-4.91 (m, 1H), 4.15 (s, 3H), 3.72-3.61 (m, 3H), 3.47-3.28 (m, 3H),2.54-2.44 (m, 1H), 2.26-2.16 (m, 1H). MS=471 (MH)+.

Example 3281-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

1-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-1H-pyrrolo[2,3-b]pyridine-4-carbonitrilewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.176 mmol) and1H-Pyrrolo[2,3-b]pyridine-4-carbonitrile (30.0 mg, 0.210 mmol) in ananalogous manner to Example 303c. Product isolated as thetrifluoroacetic acid salt as an off-white lyophilate (0.068 g, 71%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.83 (s, 1H), 9.31 (s, 1H), 8.89 (brs, 2H), 8.79-8.75 (m, 4H), 8.72 (d, J=4.9 Hz, 1H), 8.37 (d, J=5.2 Hz,1H), 8.30 (d, J=5.6 Hz, 1H), 7.87 (d, J=4.9 Hz, 1H), 7.04 (d, J=3.9 Hz,1H), 5.00-4.91 (m, 1H), 3.83-3.74 (m, 1H), 3.57-3.39 (m, 3H), 2.54-2.44(m, 1H), 2.37-2.30 (m, 1H). MS=434 (MH)+.

Example 329{5-Methoxy-2-[2-(5-phenyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{5-Methoxy-2-[2-(5-phenyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.164 mmol) and5-Phenyl-pyridin-2-ylamine (31.0 mg, 0.182 mmol) in an analogous mannerto Example 303c. Product isolated as the trifluoroacetic acid salt as ayellow lyophilate (0.043 g, 43%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):9.04-8.85 (m, 3H), 8.66-8.61 (m, 2H), 8.48 (d, J=5.5 Hz, 1H), 8.44 (s,1H), 8.23-8.15 (m, 2H), 8.00-7.95 (m, 1H), 7.82-7.75 (m, 1H), 7.74-7.71(m, 2H), 7.51 (t, J=7.6 Hz, 2H), 7.41 (t, J=7.1 Hz, 1H), 5.07-5.00 (m,1H), 4.18 (s, 3H), 3.76-3.66 (m, 1H), 3.54-3.30 (m, 3H), 2.55-2.45 (m,1H), 2.30-2.20 (m, 1H). MS=491 (MH)+.

Example 330{5-Methoxy-2-[2-(6-morpholin-4-yl-pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine{5-Methoxy-2-[2-(6-morpholin-4-yl-pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.164 mmol) and6-Morpholin-4-yl-pyridin-3-ylamine (33.0 mg, 0.184 mmol) in an analogousmanner to Example 303c. Product isolated as the trifluoroacetic acidsalt as a tan lyophilate (0.033 g, 33%)

¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.02-8.82 (m, 3H), 8.60-8.52 (m, 1H),8.41 (s, 1H), 8.26 (d, J=4.8 Hz, 1H), 8.17 (d, J=4.4 Hz, 1H), 8.00-7.95(m, 1H), 7.89 (s, 1H), 7.72-7.68 (m, 1H), 7.10-6.98 (m, 1H), 5.05-4.95(m, 1H), 4.16 (s, 3H), 3.76-3.63 (m, 5H), 3.50-3.29 (m, 7H), 2.54-2.45(m, 1H), 2.26-2.16 (m, 1H). MS=500 (MH)+.

Example 331(5-Methoxy-2-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine

(5-Methoxy-2-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.164 mmol) and6-(4-Methyl-piperazin-1-yl)-pyridin-3-ylamine (35.0 mg, 0.182 mmol) inan analogous manner to Example 303c. Product isolated as thebis-trifluoroacetic acid salt as a brown lyophilate (0.036 g, 29%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.69 (br s, 1H), 9.26 (br s, 1H),9.06-8.81 (m, 3H), 8.51 (d, J=2.6 Hz, 1H), 8.40 (s, 1H), 8.25 (d, J=5.5Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 8.04 (dd, J=9.1, 2.6 Hz, 1H), 7.86 (s,1H), 7.67 (d, J=5.3 Hz, 1H), 6.98 (d, J=9.0 Hz, 1H), 5.04-4.98 (m, 1H),4.32-4.26 (m, 2H), 4.16 (s, 3H), 3.71-3.65 (m, 1H), 3.55-3.50 (m, 2H),3.50-3.30 (m, 3H), 3.16-3.01 (m, 4H), 2.86 (d, J=4.3 Hz, 3H), 2.53-2.43(m, 1H), 2.26-2.16 (m, 1H).

MS=513 (MH)+.

Example 3322-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile

2-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrilewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.164 mmol) and2-Amino-isonicotinonitrile (22.0 mg, 0.185 mmol) in an analogous mannerto Example 303c. Product isolated as the trifluoroacetic acid salt as ayellow lyophilate (0.014 g, 15%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.42 (s, 1H), 8.98-8.80 (m, 3H), 8.60 (s, 1H), 8.51 (d, J=5.1 Hz, 1H),8.48 (d, J=5.3 Hz, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 8.16 (d, J=5.8 Hz,1H), 7.92 (dd, J=5.2, 1.3 Hz, 1H), 7.32 (dd, J=5.0, 1.3 Hz, 1H),5.03-4.95 (m, 1H), 4.17 (s, 3H), 3.75-3.66 (m, 1H), 3.50-3.30 (m, 3H),2.55-2.45 (m, 1H), 2.28-2.18 (m, 1H). MS=440 (MH)+.

Example 333{2-[2-(4-Imidazol-1-ylmethyl-phenylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(4-Imidazol-1-ylmethyl-phenylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.164 mmol) and4-Imidazol-1-ylmethyl-phenylamine (32.0 mg, 0.185 mmol) in an analogousmanner to Example 303c. Product isolated as the trifluoroacetic acidsalt as a yellow-orange lyophilate (0.037 g, 37%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 9.53 (s, 1H), 9.24-9.22 (m, 1H), 9.18-8.92 (m, 2H),8.82 (s, 1H), 8.40 (s, 1H), 8.33 (d, J=5.3 Hz, 1H), 8.18 (d, J=6.3 Hz,1H), 7.94 (s, 1H), 7.81 (d, J=8.6 Hz, 2H), 7.78 (t, J=1.7 Hz, 1H), 7.74(dd, J=5.2, 1.3 Hz, 1H), 7.70 (t, J=1.7 Hz, 1H), 7.37 (d, J=8.7 Hz, 2H),5.36 (s, 2H), 5.08-4.99 (m, 1H), 4.16 (s, 3H), 3.74-3.64 (m, 1H),3.52-3.29 (m, 3H), 2.53-2.43 (m, 1H), 2.26-2.16 (m, 1H). MS=494 (MH)+.

Example 3342-Phenyl-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

2-Phenyl-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.176 mmol) and Benzeneacetamide (27.0mg, 0.200 mmol) in an analogous manner to Example 303c. Product isolatedas the trifluoroacetic acid salt as a tan lyophilate (0.036 g, 38%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.89 (s, 1H), 9.25 (s, 1H), 9.14 (s,1H), 8.90 (br s, 2H), 8.73-8.69 (m, 2H), 8.50 (dd, J=5.2, 0.6 Hz, 1H),8.25 (d, J=5.2 Hz, 1H), 8.09 (dd, J=5.2, 1.4 Hz, 1H), 7.41-7.24 (m, 5H),4.93-4.85 (m, 1H), 3.79 (s, 2H), 3.75-3.65 (m, 1H), 3.51-3.33 (m, 3H),2.47-2.37 (m, 1H), 2.31-2.21 (m, 1H). MS=426 (MH)+.

Example 3352-(4-Methoxy-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

2-(4-Methoxy-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.176 mmol) and 4-Methoxyphenylacetamide(33.0 mg, 0.200 mmol) in an analogous manner to Example 303c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.021g, 21%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.81 (s, 1H), 9.24 (s, 1H),9.13 (s, 1H), 8.88 (br s, 2H), 8.71 (d, J=5.6 Hz, 1H), 8.69 (d, J=4.8Hz, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.25 (d, J=5.3 Hz, 1H), 8.08 (dd,J=5.1, 1.5 Hz, 1H), 7.30 (d, J=8.7 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H),4.93-4.85 (m, 1H), 3.75-3.65 (m, 6H), 3.49-3.34 (m, 3H), 2.47-2.37 (m,1H), 2.31-2.21 (m, 1H). MS=456 (MH)+.

Example 3362-(2-Methoxy-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

336a) 2-(2-Methoxy-phenyl)-acetamide was prepared from2-Methoxybenzeneacetic acid (1.0 g, 6.0 mmol) in an analogous manner toExample 13a. Product isolated as a white solid (0.64 g, 64%). ¹HNMR (400MHz, d6-DMSO, δ, ppm): 7.24-7.18 (m, 2H), 7.15 (dd, J=7.5, 1.6 Hz, 1H),6.95 (d, J=7.7 Hz, 1H), 6.90-6.84 (m, 1H), 6.81 (br s, 1H), 3.75 (s,3H), 3.35 (s, 2H). MS=166 (MH)+.

336b)2-(2-Methoxy-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.176 mmol;) and2-(2-Methoxy-phenyl)-acetamide (32.0 mg, 0.194 mmol) in an analogousmanner to Example 303c. Product isolated as the trifluoroacetic acidsalt as a tan lyophilate (0.048 g, 48%). ¹HNMR (400 MHz, d6-DMSO, δ,ppm): 10.66 (s, 1H), 9.24 (s, 1H), 9.12 (s, 1H), 8.84 (br s, 2H), 8.71(d, J=5.7 Hz, 1H), 8.69-8.65 (m, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.25 (d,J=5.3 Hz, 1H), 8.08 (dd, J=5.3, 1.3 Hz, 1H), 7.30-7.23 (m, 2H), 7.01 (d,J=7.8 Hz, 1H), 6.95-6.90 (m, 1H), 4.93-4.85 (m, 1H), 3.80-3.74 (m, 5H),3.72-3.63 (m, 1H), 3.49-3.30 (m, 3H), 2.45-2.37 (m, 1H), 2.30-2.20 (m,1H). MS=456 (MH)+.

Example 3372-(3-Methoxy-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

2-(3-Methoxy-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (75.0 mg, 0.176 mmol) and2-(3-Methoxy-phenyl)-acetamide (32.0 mg, 0.194 mmol) in an analogousmanner to Example 303c. Product isolated as the trifluoroacetic acidsalt as a tan lyophilate (0.099 g). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.86 (s, 1H), 9.25 (s, 1H), 9.13 (s, 1H), 8.89 (br s, 2H), 8.73-8.68(m, 2H), 8.50 (d, J=5.2 Hz, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.09 (dd,J=5.2, 1.5 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 6.98-6.94 (m, 2H), 6.86-6.82(m, 1H), 4.94-4.85 (m, 1H), 3.77-3.65 (m, 6H), 3.51-3.34 (m, 3H),2.47-2.37 (m, 1H), 2.31-2.21 (m, 1H). MS=456 (MH)+.

Example 338{2-[2-(4-Methyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(4-Methyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and4-Methyl-pyridin-2-ylamine (31.0 mg, 0.287 mmol) in an analogous mannerto Example 303c. Product isolated as the trifluoroacetic acid salt as apale yellow lyophilate (0.107 g). ¹HNMR=31550651 (400 MHz, d6-DMSO, δ,ppm): 9.28-9.27 (m, 1H), 8.99 (br s, 2H), 8.84-8.79 (m, 1H), 8.77-8.74(m, 1H), 8.55 (d, J=5.4 Hz, 1H), 8.42-8.36 (m, 1H), 8.31-8.26 (m, 2H),8.18-8.14 (m, 1H), 7.27 (s, 1H), 7.16-7.12 (m, 1H), 5.04-4.94 (m, 1H),3.78-3.68 (m, 1H), 3.54-3.34 (m, 3H), 2.48 (s, 3H), 2.46-2.36 (m, 1H),2.32-2.22 (m, 1H). MS=399 (MH)+.

Example 339{2-[2-(4-Chloro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(4-Chloro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (105.0 mg, 0.2460 mmol) and4-Chloro-pyridin-2-ylamine (37.0 mg, 0.288 mmol) in an analogous mannerto Example 303c. Product isolated as the trifluoroacetic acid salt as apale yellow lyophilate (0.124 g, 96%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.43 (br s, 1H), 9.26 (s, 1H), 8.90 (br s, 2H), 8.75-8.70 (m, 2H), 8.64(s, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.30-8.25 (m, 2H), 8.01 (s, 1H), 7.95(d, J=5.4 Hz, 1H), 7.07 (d, J=5.3 Hz, 1H), 4.97-4.89 (m, 1H), 3.80-3.70(m, 1H), 3.53-3.35 (m, 3H), 2.49-2.39 (m, 1H), 2.34-2.24 (m, 1H). MS=419(MH)+.

Example 340[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrazin-2-yl-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrazin-2-yl-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (352.0 mg, 0.7704 mmol) and 2-Aminopyrazine (81mg, 0.85 mmol) in an analogous manner to Example 303c. Product wasisolated as the free base as an off-white solid (0.050 g, 16%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 10.22 (s, 1H), 9.17 (d, J=1.4 Hz, 1H), 8.83(s, 1H), 8.72 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 8.28 (dd,J=1.6, 2.6 Hz, 1H), 8.12 (d, J=2.7 Hz, 1H), 7.86 (dd, J=1.3, 5.2 Hz,1H), 4.07 (s, 3H), 3.70-3.65 (m, 4H), 2.90-2.85 (m, 4H). MS=416 (MH)+.

Example 3416-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-nicotinonitrile

6-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-nicotinonitrilewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and6-Amino-nicotinonitrile (33.0 mg, 0.277 mmol) in an analogous manner toExample 303c. Product isolated as the trifluoroacetic acid salt as apale yellow lyophilate (0.016 g, 13%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.60 (s, 1H), 9.26 (s, 1H), 8.92-8.80 (m, 3H), 8.75-8.72 (m, 2H), 8.69(d, J=4.6 Hz, 1H), 8.48 (d, J=5.3 Hz, 1H), 8.28 (d, J=5.2 Hz, 1H), 8.10(dd, J=8.9, 2.3 Hz, 1H), 8.00 (dd, J=5.2, 1.3 Hz, 1H), 7.90 (d, J=8.9Hz, 1H), 4.94-4.89 (m, 1H), 3.78-3.70 (m, 1H), 3.51-3.35 (m, 3H),2.46-2.40 (m, 1H), 2.35-2.25 (m, 1H). MS=410 (MH)+.

Example 3422-[4-(4-Piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinonitrile

342a)4-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester was prepared from2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol (500.0 mg, 1.933mmol) and tert-Butyl 1-Piperazinecarboxylate (432.0 mg, 2.320 mmol) inan analogous manner to [B016]. Product isolated as a yellow foam (0.817g, 99%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.30 (s, 1H), 8.64-8.60 (m,2H), 8.38-8.35 (m, 2H), 8.01-7.98 (m, 1H), 4.06-4.01 (m, 4H), 3.67-3.62(m, 4H), 3.32 (s, 3H), 1.45 (s, 9H). MS=427 (MH)+.

342b)2-[4-(4-Piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinonitrilewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and2-Amino-isonicotinonitrile (31.0 mg, 0.260 mmol) in an analogous mannerto Example 303c. Product isolated as the trifluoroacetic acid salt as apale yellow lyophilate (0.015 g, 12%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.44 (s, 1H), 9.36 (s, 1H), 8.90 (br s, 2H), 8.69-8.66 (m, 2H),8.53-8.48 (m, 2H), 8.36 (s, 1H), 8.04 (d, J=5.7 Hz, 1H), 7.95 (dd,J=5.3, 1.3 Hz, 1H), 7.33 (dd, J=5.1, 1.3 Hz, 1H), 4.18-4.13 (m, 4H),3.42-3.37 (m, 4H). MS=410 (MH)+.

Example 343{2-[2-(4-Morpholin-4-yl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(4-Morpholin-4-yl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and4-Morpholin-4-yl-pyridin-2-ylamine (47.0 mg, 0.262 mmol)[prepared asdescribed in WO2006/040520] in an analogous manner to Example 303c.Product isolated the free base as a pale yellow solid (0.016 g, 14%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.51 (s, 1H), 9.17 (s, 1H), 8.86 (s,1H), 8.67-8.52 (m, 2H), 8.35-8.27 (m, 2H), 7.95 (d, J=6.0 Hz, 1H),7.81-7.78 (m, 1H), 7.30-7.27 (m, 1H), 6.52-6.47 (m, 1H), 4.97-4.75 (m,1H), 3.77-3.72 (m, 4H), 3.35-3.30 (m, 1H), 3.26-3.22 (m, 4H), 3.06-2.98(m, 1H), 2.92-2.84 (m, 2H), 2.31-2.21 (m, 1H), 1.93-1.83 (m, 1H). MS=470(MH)+.

Example 3446-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-nicotinonitrile

344a) 2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-olwas prepared from 2-Chloro-isonicotinonitrile (0.96 g, 6.9 mmol) and3-Amino-5-methoxy-isonicotinic acid (0.97 g, 5.8 mmol) in an analogousmanner to example 1501a. Product isolated as a tan solid (0.774 g, 46%).¹HNMR (400 MHz, d1-TFA, δ, ppm): 9.24 (s, 1H), 9.11 (d, J=6.2 Hz, 1H),8.93 (s, 1H), 8.85 (d, J=6.0 Hz, 1H), 8.71 (s, 1H), 4.36 (s, 3H). MS=289(MH)+.

344b)R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester was prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (0.50 g,1.7 mmol) and (R)-3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester(0.32 mL, 1.9 mmol) in an analogous manner to [B016]. Product isolatedas a light brown solid (0.50 g, 63%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):8.84 (s, 1H), 8.61 (d, J=5.0 Hz, 1H), 8.39 (s, 1H), 8.36-8.32 (m, 2H),8.24-8.17 (m, 1H), 5.09-4.92 (m, 1H), 4.14 (s, 3H), 3.86-3.72 (m, 1H),3.55-3.32 (m, 3H), 2.37-2.25 (m, 1H), 2.21-2.07 (m, 1H), 1.45-1.38 (m,9H). MS=457 (MH)+.

344c)6-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-nicotinonitrilewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (160.0 mg, 0.3502 mmol) and6-Amino-nicotinonitrile (50.0 mg, 0.420 mmol) in an analogous manner toExample 303c. Product isolated as the trifluoroacetic acid salt as apale yellow lyophilate (0.043 g, 22%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.60 (s, 1H), 9.00-8.80 (m, 4H), 8.72 (d, J=2.2 Hz, 1H), 8.48 (d, J=5.3Hz, 1H), 8.42 (s, 1H), 8.15 (d, J=5.8 Hz, 1H), 8.10 (dd, J=8.9, 2.4 Hz,1H), 7.97 (dd, J=5.3, 1.5 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 5.01-4.93 (m,1H), 4.17 (s, 3H), 3.75-3.65 (m, 1H), 3.52-3.30 (m, 3H), 2.55-2.45 (m,1H), 2.29-2.19 (m, 1H). MS=440 (MH)+.

Example 345{2-[2-(5-Methyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(5-Methyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and5-Methyl-pyridin-2-ylamine (30.0 mg, 0.277 mmol) in an analogous mannerto Example 303c. Product isolated as the trifluoroacetic acid salt as apale yellow lyophilate (0.033 g, 27%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):9.27 (s, 1H), 8.93 (br s, 2H), 8.81-8.77 (m, 1H), 8.76 (d, J=5.6 Hz,1H), 8.52-8.45 (m, 2H), 8.29 (d, J=5.5 Hz, 1H), 8.20 (s, 1H), 8.08 (brs, 1H), 7.87 (br s, 1H), 7.49 (br s, 1H), 5.00-4.90 (m, 1H), 3.79-3.69(m, 1H), 3.55-3.35 (m, 3H), 2.47-2.37 (m, 1H), 2.34-2.24 (m, 4H). MS=399(MH)+.

Example 346{2-[2-(5-Chloro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(5-Chloro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and2-Amino-5-chloropyridine (36.0 mg, 0.280 mmol) in an analogous manner toExample 303c. Product isolated as the trifluoroacetic acid salt as ayellow lyophilate (0.081 g, 65%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.36 (br s, 1H), 9.26 (s, 1H), 8.89 (br s, 2H), 8.74 (d, J=5.6 Hz, 1H),8.71 (d, J=4.8 Hz, 1H), 8.67 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 8.34-8.32(m, 1H), 8.27 (d, J=5.1 Hz, 1H), 7.93 (d, J=5.5 Hz, 1H), 7.88-7.82 (m,2H), 4.97-4.87 (m, 1H), 3.79-3.70 (m, 1H), 3.55-3.35 (m, 3H), 2.50-2.40(m, 1H), 2.34-2.24 (m, 1H). MS=419 (MH)+.

Example 3472-[2-(Pyrimidin-4-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(Pyrimidin-4-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and Pyrimidin-4-ylamine(27.0 mg, 0.284 mmol) in an analogous manner to Example 303c. Productisolated as the trifluoroacetic acid salt as an off-white lyophilate(0.033 g, 28%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 11.07 (br s, 1H), 9.26(s, 1H), 9.07 (br s, 2H), 8.95 (s, 1H), 8.87 (d, J=5.3 Hz, 1H), 8.84 (s,1H), 8.73 (d, J=5.6 Hz, 1H), 8.56-8.53 (m, 2H), 8.35 (d, J=5.5 Hz, 1H),8.10 (d, J=5.2, 1.2 Hz, 1H), 7.97-7.90 (m, 1H), 5.00-4.92 (m, 1H),3.79-3.69 (m, 1H), 3.55-3.35 (m, 3H), 2.49-2.39 (m, 1H), 2.35-2.25 (m,1H). MS=386 (MH)+.

Example 3482-(3-Cyano-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

348a) 2-(3-Cyano-phenyl)-acetamide was prepared from(3-Cyano-phenyl)-acetic acid (1.0 g, 6.2 mmol) in an analogous manner toExample 313a. Product isolated as an off-white solid (0.50 g, 50%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 7.72-7.69 (m, 2H), 7.61-7.58 (m, 1H),7.56-7.50 (m, 2H), 6.97 (br s, 1H), 3.47 (s, 2H). MS=161 (MH)+.

348b)2-(3-Cyano-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and2-(3-Cyano-phenyl)-acetamide (45.0 mg, 0.281 mmol) in an analogousmanner to Example 303c and Example Ic. Product isolated as thetrifluoroacetic acid salt as a pale yellow lyophilate (0.125 g, 94%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.97 (s, 1H), 9.24 (s, 1H), 9.12 (s,1H), 8.90 (br s, 2H), 8.73-8.69 (m, 2H), 8.51 (dd, J=5.1, 0.5 Hz, 1H),8.25 (dd, J=5.6, 0.7 Hz, 1H), 8.10 (dd, J=5.2, 1.5 Hz, 1H), 7.84-7.82(m, 1H), 7.78-7.75 (m, 1H), 7.74-7.70 (m, 1H), 7.58 (t, J=7.8 Hz, 1H),4.94-4.85 (m, 1H), 3.90 (s, 2H), 3.74-3.64 (m, 1H), 3.51-3.33 (m, 3H),2.47-2.37 (m, 1H), 2.30-2.20 (m, 1H). MS=451 (MH)+.

Example 3492-(4-Cyano-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

349a) 2-(4-Cyano-phenyl)-acetamide was prepared from(4-Cyano-phenyl)-acetic acid (1.0 g, 6.2 mmol) in an analogous manner toExample 313a. Product isolated as an off-white solid (0.71 g, 71%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 7.77 (d, J=8.3 Hz, 2H), 7.55 (br s,1H), 7.45 (d, J=8.3 Hz, 2H), 6.98 (br s, 1H), 3.49 (s, 2H). MS=161(MH)+. 349b)2-(4-Cyano-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (120.0 mg, 0.2811 mmol) and2-(4-Cyano-phenyl)-acetamide (45.0 mg, 0.281 mmol) in an analogousmanner to Example 303c and Example 1c. Product isolated as thetrifluoroacetic acid salt as a pale orange lyophilate (0.148 g, 93%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.98 (s, 1H), 9.23 (s, 1H), 9.12 (s,1H), 8.87 (br s, 2H), 8.73-8.68 (m, 2H), 8.51 (dd, J=5.1, 0.6 Hz, 1H),8.25 (dd, J=5.7, 0.6 Hz, 1H), 8.10 (dd, J=5.1, 1.4 Hz, 1H), 7.83 (d,J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 4.93-4.84 (m, 1H), 3.92 (s, 2H),3.73-3.64 (m, 1H), 3.51-3.32 (m, 3H), 2.47-2.36 (m, 1H), 2.30-2.21 (m,1H). MS=451 (MH)+.

Example 350(R)-Pyrrolidin-3-yl-{2-[2-(4-trifluoromethyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-amine

(R)-Pyrrolidin-3-yl-{2-[2-(4-trifluoromethyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and4-Trifluoromethyl-pyridin-2-ylamine (46.0 mg, 0.284 mmol) in ananalogous manner to Example 303c and Example Ic. Product isolated as thetrifluoroacetic acid salt as a pale yellow lyophilate (0.127 g, 95%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.57 (s, 1H), 9.26 (d, J=0.4 Hz, 1H),8.94 (br s, 2H), 8.75-8.72 (m, 2H), 8.69 (s, 1H), 8.56 (d, J=5.1 Hz,1H), 8.47 (d, J=5.4 Hz, 1H), 8.28 (dd, J=5.7, 0.6 Hz, 1H), 8.26 (s, 1H),7.97 (dd, J=5.4, 1.5 Hz, 1H), 7.25 (dd, J=5.9, 1.0 Hz, 1H), 4.99-4.90(m, 1H), 3.80-3.71 (m, 1H), 3.55-3.35 (m, 3H), 2.48-2.40 (m, 1H),2.34-2.24 (m, 1H). MS=453 (MH)+.

Example 351(R)-Pyrrolidin-3-yl-{2-[2-(5-trifluoromethyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-amine

(R)-Pyrrolidin-3-yl-{2-[2-(5-trifluoromethyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and5-Trifluoromethyl-pyridin-2-ylamine (46.0 mg, 0.284 mmol) in ananalogous manner to Example 303c and Example Ic. Product isolated as atrifluoroacetic acid salt as a pale yellow lyophilate (0.102 g, 76%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.64 (s, 1H), 9.27 (d, J=0.6 Hz, 1H),8.94 (br s, 2H), 8.75-7.73 (m, 3H), 8.66-8.63 (m, 1H), 8.48 (dd, J=5.2,0.3 Hz, 1H), 8.28 (dd, J=5.6, 0.7 Hz, 1H), 8.08 (dd, J=9.1, 2.5 Hz, 1H),8.03-7.98 (m, 2H), 4.99-4.90 (m, 1H), 3.80-3.70 (m, 1H), 3.55-3.35 (m,3H), 2.50-2.40 (m, 1H), 2.34-2.24 (m, 1H). MS=453 (MH)+.

Example 3522-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinonitrile

352a)4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester was prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (2.0 g,6.9 mmol) and tert-Butyl 1-Piperazinecarboxylate (1.5 g, 8.3 mmol;Supplier=Aldrich) in an analogous manner to [B016]. Product isolated asan off-white solid (1.35 g, 43%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.88(s, 1H), 8.61 (dd, J=4.9, 0.8 Hz, 1H), 8.39 (s, 1H), 8.34-8.31 (m, 2H),4.09 (s, 3H), 3.72-3.67 (m, 4H), 3.57-3.52 (m, 4H), 1.44 (s, 9H).MS=457, 459 (MH)+.

352b)2-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinonitrilewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-Amino-isonicotinonitrile (31.0 mg, 0.260 mmol) in an analogous mannerto Example 303c and Example 1c. Product isolated as the trifluoroaceticacid salt as a pale yellow lyophilate (0.105 g, 86%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 10.49 (s, 1H), 8.93 (s, 1H), 8.88 (br s, 2H), 8.64 (s,1H), 8.51 (dd, J=5.1, 0.6 Hz, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.43 (s, 1H),8.34 (s, 1H), 7.92 (dd, J=5.4, 1.4 Hz, 1H), 7.34 (dd, J=5.0, 1.3 Hz,1H), 4.11 (s, 3H), 3.93-3.88 (m, 4H), 3.37-3.30 (m, 4H). MS=440 (MH)+.

Example 3536-[4-(5-Methoxy-4-piperazin-1-yl-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-nicotinonitrile

6-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-nicotinonitrilewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and6-Amino-nicotinonitrile (31.0 mg, 0.260 mmol) in an analogous manner toExample 303c and Example 1c. Product isolated as the trifluoroaceticacid salt as pale yellow lyophilate (0.109 g, 89%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 10.64 (s, 1H), 8.93 (s, 1H), 8.90-8.82 (m, 3H), 8.72(d, J=2.2 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H), 8.43 (s, 1H), 8.11 (dd,J=8.9, 2.4 Hz, 1H), 7.96 (dd, J=5.2, 1.4 Hz, 1H), 7.92 (d, J=8.9 Hz,1H), 4.11 (s, 3H), 3.93-3.88 (m, 4H), 3.37-3.31 (m, 4H). MS=440 (MH)+.

Example 354{4-[5-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine

354a)2-(2-Chloro-pyridin-4-yl)-5-methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-pyrido[3,4-d]pyrimidinewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (190.0mg, 0.6581 mmol) and 4-Piperidin-4-yl-morpholine (134.0 mg, 0.7871 mmol)in an analogous manner to [B016]. Product isolated as a red-orange solid(0.146 g, 50%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.84 (s, 1H), 8.60(dd, J=4.9, 0.6 Hz, 1H), 8.36 (s, 1H), 8.32-8.29 (m, 2H), 4.28 (d,J=11.6 Hz, 2H), 4.08 (s, 3H), 3.60-3.55 (m, 4H), 3.15 (t, J=11.6 Hz,2H), 2.53-2.46 (m, 5H), 1.96 (d, J=11.3 Hz, 2H), 1.61-1.49 (m, 2H). (400MHz, CDCl3, 6, ppm): 8.97 (s, 1H), 8.52 (d, J=4.9 Hz, 1H), 8.37 (s, 1H),8.28 (dd, J=5.2, 1.3 Hz, 1H), 8.21 (s, 1H), 4.36 (d, J=13.2 Hz, 2H),4.09 (s, 3H), 3.77-3.73 (m, 4H), 3.18-3.09 (m, 2H), 2.63-2.58 (m, 4H),2.53-2.43 (m, 1H), 2.06 (d, J=12.7 Hz, 2H), 1.74-1.63 (m, 2H). MS=441,443 (MH)+.

354b){4-[5-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-aminewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-pyrido[3,4-d]pyrimidine(80.0 mg, 0.181 mmol) and Aniline (18.6 L, 0.204 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.108 g, 97%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.74 (br s, 1H), 9.46 (br s, 1H), 8.87 (s,1H), 8.39 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 7.94 (s, 1H), 7.75-7.73 (m,2H), 7.70 (dd, J=5.3, 1.3 Hz, 1H), 7.31 (t, J=7.6 Hz, 2H), 6.95 (t,J=7.2 Hz, 1H), 4.42 (d, J=12.6 Hz, 2H), 4.12 (s, 3H), 4.04 (d, J=11.7Hz, 2H), 3.67 (t, J=12.1 Hz, 2H), 3.62-3.54 (m, 1H), 3.51 (d, J=12.1 Hz,2H), 3.22-3.10 (m, 4H), 2.25 (d, J=10.4 Hz, 2H), 1.85-1.72 (m, 2H).MS=498 (MH)+.

Example 3552-(4-Cyano-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide

2-(4-Cyano-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-(4-Cyano-phenyl)-acetamide (45.0 mg, 0.281 mmol) in an analogousmanner to Example 303c and Example 1c. Product isolated as thetrifluoroacetic acid salt as a pale orange lyophilate (0.102 g, 78%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.99 (s, 1H), 9.08 (s, 1H), 8.90 (s,1H), 8.83 (br s, 2H), 8.51 (dd, J=5.2, 0.6 Hz, 1H), 8.41 (s, 1H), 8.06(dd, J=5.1, 1.5 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H),4.09 (s, 3H), 3.92 (s, 2H), 3.87-3.83 (m, 4H), 3.31 (br s, 4H). MS=481(MH)+.

Example 3562-(3-Cyano-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide

2-(3-Cyano-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-(3-Cyano-phenyl)-acetamide (45.0 mg, 0.281 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as a paleyellow lyophilate (0.125 g, 96%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.97 (s, 1H), 9.07 (s, 1H), 8.91 (s, 1H), 8.87 (br s, 2H), 8.52 (dd,J=5.1, 0.4 Hz, 1H), 8.41 (s, 1H), 8.06 (dd, J=5.2, 1.4 Hz, 1H),7.84-7.82 (m, 1H), 7.78-7.74 (m, 1H), 7.73-7.70 (m, 1H), 7.57 (t, J=7.7Hz, 1H), 4.09 (s, 3H), 3.89 (s, 2H), 3.87-3.83 (m, 4H), 3.31 (br s, 4H).MS=481 (MH)+.

Example 357{2-[2-(5-Morpholin-4-yl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(5-Morpholin-4-yl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2342 mmol) and5-Morpholin-4-yl-pyridin-2-ylamine (48.0 mg, 0.268 mmol) [prepared asdescribed in Toogood, P. L.; et. al. J. Med. Chem. 2005, 48(7),2388-2406.] in an analogous manner to Example 303c and Example 1501c.Product isolated as the trifluoroacetic acid salt as an orangelyophilate (0.103 g, 60%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.27 (s,1H), 8.93 (br s, 2H), 8.83-8.79 (m, 1H), 8.76 (d, J=5.5 Hz, 1H), 8.14(d, J=5.9 Hz, 1H), 8.40 (s, 1H), 8.26 (d, J=5.5 Hz, 1H), 8.07-8.01 (m,1H), 7.94 (d, J=2.9 Hz, 1H), 7.87-7.86 (m, 1H), 7.49-7.40 (m, 1H),5.00-4.91 (m, 1H), 3.81-3.77 (m, 4H), 3.76-3.69 (m, 1H), 3.55-3.36 (m,3H), 3.17-3.13 (m, 4H), 2.47-2.37 (m, 1H), 2.33-2.23 (m, 1H). MS=470(MH)+.

Example 358{2-[2-(2-Methoxy-4-morpholin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(2-Methoxy-4-morpholin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (115.0 mg, 0.2694 mmol) and2-Methoxy-4-morpholin-4-yl-phenylamine (58.0 mg, 0.278 mmol) [preparedas described in WO2008/051547] in an analogous manner to Example 303cand Example 1501c. Product isolated as the trifluoroacetic acid salt asan orange-brown lyophilate (0.155 g, 93%). ¹HNMR (400 MHz, d6-DMSO, δ,ppm): 10.25 (br s, 1H), 9.27 (s, 1H), 9.08 (br s, 2H), 8.87 (d, J=5.1Hz, 1H), 8.77 (d, J=5.6 Hz, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.16 (s, 1H),7.98 (d, J=6.5 Hz, 1H), 7.81 (dd, J=6.6, 1.3 Hz, 1H), 7.31 (d, J=8.5 Hz,1H), 6.76 (d, J=2.3 Hz, 1H), 6.64 (dd, J=8.8, 2.4 Hz, 1H), 4.94-4.85 (m,1H), 3.82 (s, 3H), 3.80-3.75 (m, 4H), 3.73-3.63 (m, 1H), 3.55-3.33 (m,3H), 3.25-3.20 (m, 4H), 2.43-2.34 (m, 1H), 2.31-2.22 (m, 1H). MS=499(MH)+.

Example 359(2-Methoxy-4-morpholin-4-yl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(2-Methoxy-4-morpholin-4-yl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (115.0 mg, 0.2517 mmol) and2-Methoxy-4-morpholin-4-yl-phenylamine (55.0 mg, 0.264 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe trifluoroacetic acid salt as an orange-brown lyophilate (0.150 g,92%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.25 (br s, 1H), 9.05 (br s,2H), 8.93 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 8.00 (d, J=6.6 Hz, 1H),7.76 (dd, J=6.5, 1.3 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 6.76 (d, J=2.4 Hz,1H), 6.64 (dd, J=8.7, 2.4 Hz, 1H), 4.11 (s, 3H), 3.91-3.86 (m, 4H), 3.81(s, 3H), 3.80-3.76 (m, 4H), 3.32 (br s, 4H), 3.25-3.21 (m, 4H). MS=529(MH)+.

Example 360{5-Methoxy-2-[2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{5-Methoxy-2-[2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-Methoxy-4-morpholin-4-yl-phenylamine (55.0 mg, 0.264 mmol;) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe trifluoroacetic acid salt as an orange-brown lyophilate (0.057 g,40%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.13 (br s, 1H), 9.21-9.00 (m,2H), 8.86 (s, 1H), 8.46 (s, 1H), 8.26 (d, J=6.2 Hz, 1H), 8.10 (s, 1H),7.99 (d, J=6.4 Hz, 1H), 7.74 (dd, J=6.4, 1.2 Hz, 1H), 7.33 (d, J=8.2 Hz,1H), 6.76 (d, J=2.4 Hz, 1H), 6.63 (dd, J=8.7, 2.4 Hz, 1H), 5.01-4.91 (m,1H), 4.17 (s, 3H), 3.81 (s, 3H), 3.80-3.75 (m, 4H), 3.69-3.59 (m, 1H),3.53-3.40 (m, 2H), 3.37-3.26 (m, 1H), 3.25-3.20 (m, 4H), 2.51-2.41 (m,1H), 2.26-2.16 (m, 1H). MS=529 (MH)+.

Example 361(5-Methoxy-2-{2-[4-(tetrahydro-pyran-4-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine

(5-Methoxy-2-{2-[4-(tetrahydro-pyran-4-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and4-(Tetrahydro-pyran-4-yl)-phenylamine (43.0 mg, 0.243 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe trifluoroacetic salt as a yellow lyophilate (0.109 g, 81%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.41 (br s, 1H), 8.99 (br s, 1H), 8.88 (brs, 1H), 8.83 (s, 1H), 8.41 (s, 1H), 8.28 (d, J=5.5 Hz, 1H), 8.16 (d,J=6.2 Hz, 1H), 7.93 (s, 1H), 7.69 (dd, J=5.5, 1.2 Hz, 1H), 7.64 d, J=8.5Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 5.05-4.95 (m, 1H), 4.16 (s, 3H),3.98-3.92 (m, 2H), 3.72-3.63 (m, 1H), 3.50-3.28 (m, 5H), 2.76-2.68 (m,1H), 2.50-2.43 (m, 1H), 2.27-2.17 (m, 1H), 1.73-1.60 (m, 4H). MS=498(MH)+.

Example 362[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[4-(tetrahydro-pyran-4-yl)-phenyl]-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[4-(tetrahydro-pyran-4-yl)-phenyl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and4-(Tetrahydro-pyran-4-yl)-phenylamine (43.0 mg, 0.243 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe trifluoroacetic acid salt as a yellow lyophilate (0.099 g, 74%).¹HNMR (400 MHz, d6-DMSO, δ, ppm,): 9.43 (br s, 1H), 8.95-8.83 (m, 3H),8.42 (s, 1H), 8.28 (d, J=5.5 Hz, 1H), 7.93 (s, 1H), 7.68 (dd, J=5.4, 1.2Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 4.10 (s, 3H),3.98-3.92 (m, 2H), 3.90-3.85 (m, 4H), 3.44 (ddd, J=11.2, 11.2, 3.0 Hz,2H), 3.35-3.29 (m, 4H), 2.76-2.68 (m, 1H), 1.72-1.60 (m, 4H). MS=498(MH)+.

Example 363[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and4-Methyl-pyridin-2-ylamine (27.0 mg, 0.250 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.100 g, 84%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 11.72 (br s, 1H), 9.03-8.90 (m, 3H), 8.55(d, J=5.5 Hz, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.27 (d, J=6.1 Hz, 1H),8.12 (d, J=5.2 Hz, 1H), 7.27 (s, 1H), 7.14 (d, J=4.5 Hz, 1H), 4.12 (s,3H), 3.94-3.88 (m, 4H), 3.37-3.30 (m, 4H), 2.47 (s, 3H). MS=429 (MH)+.

Example 364[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methyl-pyridin-2-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methyl-pyridin-2-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (110.0 mg, 0.2407 mmol) and5-Methyl-pyridin-2-ylamine (27.0 mg, 0.250 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.122 g, 93%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 11.73 (br s, 1H), 8.98 (br s, 2H), 8.94 (s,1H), 8.54 (d, J=5.7 Hz, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.22 (s, 1H),8.12-8.08 (m, 1H), 8.00-7.94 (m, 1H), 7.42 (d, J=7.6 Hz, 1H), 4.12 (s,3H), 3.94-3.88 (m, 4H), 3.37-3.30 (m, 4H), 2.34 (s, 3H). MS=429 (MH)+.

Example 365(4-Chloro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(4-Chloro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and4-Chloro-pyridin-2-ylamine (32.0 mg, 0.249 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid as a yellow lyophilate (0.107 g, 86%). ¹HNMR (400MHz, d6-DMSO, δ, ppm): 10.56 (br s, 1H), 9.00-8.85 (m, 3H), 8.63 (s,1H), 8.46 (d, J=5.4 Hz, 1H), 8.43 (s, 1H), 8.29 (d, J=5.6 Hz, 1H), 7.99(s, 1H), 7.92 (dd, J=5.4, 1.2 Hz, 1H), 7.10 (dd, J=5.6, 1.8 Hz, 1H),4.10 (s, 1H), 3.94-3.88 (m, 4H), 3.37-3.29 (m, 4H). MS=449 (MH)+.

Example 366(5-Chloro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(5-Chloro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (110.0 mg, 0.2407 mmol) and2-Amino-5-chloropyridine (32.0 mg, 0.249 mmol) in an analogous manner toExample 303c and Example 1501c. Product isolated as the trifluoroaceticacid salt as a yellow lyophilate (0.134 g, 98%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 10.45 (br s, 1H), 8.93 (s, 1H), 8.87 (br s, 2H), 8.67(s, 1H), 8.44-8.41 (m, 2H), 8.34-8.32 (s, 1H), 7.90 (d, J=5.4 Hz, 1H),7.88-7.81 (m, 2H), 4.10 (s, 3H), 3.94-3.87 (m, 4H), 3.37-3.30 (m, 4H).MS=449 (MH)+.

Example 367[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-trifluoromethyl-pyridin-2-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-trifluoromethyl-pyridin-2-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and4-Trifluoromethyl-pyridin-2-ylamine (40.0 mg, 0.247 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe trifluoroacetic acid salt as a yellow solid (0.116 g, 88%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 10.49 (br s, 1H), 8.93 (s, 1H), 8.87 (br s,2H), 8.70 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.47 (d, J=5.3 Hz, 1H), 8.42(s, 1H), 8.30 (s, 1H), 7.91 (dd, J=5.3, 1.3 Hz, 1H), 7.25 (d, J=4.4 Hz,1H), 4.11 (s, 3H), 3.94-3.88 (m, 4H), 3.37-3.30 (m, 4H). MS=483 (MH)+.

Example 368[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-trifluoromethyl-pyridin-2-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and5-Trifluoromethyl-pyridin-2-ylamine (40.0 mg, 0.247 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe trifluoroacetic acid salt as a yellow lyophilate (0.116 g, 88%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.56 (br s, 1H), 8.94 (s, 1H), 8.88(br s, 2H), 8.78 (s, 1H), 8.64 (s, 1H), 8.47 (d, J=5.3 Hz, 1H), 8.43 (s,1H), 8.07 (dd, J=9.0, 2.3 Hz, 1H), 8.01 (d, J=9.0 Hz, 1H), 7.94 (dd,J=5.3, 1.3 Hz, 1H), 4.11 (s, 3H), 3.94-3.88 (m, 4H), 3.37-3.30 (m, 4H).MS=483 (MH)+.

Example 3692-(4-Chloro-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide

369a) 2-(4-Chloro-phenyl)-acetamide was prepared from(4-Chloro-phenyl)-acetic acid (1.0 g, 5.9 mmol) in an analogous mannerto Example 313a. Product isolated as a white solid (0.97 g, 97%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 7.47 (br s, 1H), 7.35 (d, J=8.5 Hz, 2H),7.27 (d, J=8.5 Hz, 2H), 6.90 (br s, 1H), 3.37 (s, 2H). MS=170, 172(MH)+.

369b)2-(4-Chloro-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-(4-Chloro-phenyl)-acetamide (42.0 mg, 0.248 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a pale yellow lyophilate (0.101 g, 76%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.92 (s, 1H), 9.08 (s, 1H), 8.91 (s,1H), 8.85 (br s, 2H), 8.51 (dd, J=5.1, 0.5 Hz, 1H), 8.41 (s, 1H), 8.05(dd, J=5.1, 1.5 Hz, 1H), 7.43-7.37 (m, 4H), 4.09 (s, 3H), 3.88-3.83 (m,4H), 3.79 (s, 2H), 3.35-3.28 (m, 4H). MS=490 (MH)+.

Example 3702-(3-Chloro-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide

370a) 2-(3-Chloro-phenyl)-acetamide was prepared from(3-Chloro-phenyl)-acetic acid (1.0 g, 5.9 mmol) in an analogous mannerto Example 313a. Product isolated as a white solid (0.82 g, 82%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 7.50 (br s, 1H), 7.35-7.27 (m, 3H),7.23-7.19 (m, 1H), 6.93 (br s, 1H), 3.39 (s, 2H). MS=170, 172 (MH)+.370b)2-(3-Chloro-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-(3-Chloro-phenyl)-acetamide (42.0 mg, 0.248 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.103 g, 77%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 10.94 (s, 1H), 9.08 (s, 1H), 8.91 (s, 1H),8.88 (br s, 2H), 8.51 (dd, J=5.0, 0.5 Hz, 1H), 8.41 (s, 1H), 8.06 (dd,J=5.1, 1.5 Hz, 1H), 7.47-7.45 (m, 1H), 7.41-7.32 (m, 3H), 4.09 (s, 3H),3.88-3.83 (m, 4H), 3.81 (s, 2H), 3.35-3.29 (m, 4H). MS=490 (MH)+.

Example 371N-[4-(5-Methoxy-4-piperazin-1-yl-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-phenyl-acetamide

N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-phenyl-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and Benzeneacetamide (34.0mg, 0.252 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the trifluoroacetic acid salt as a paleyellow lyophilate (0.120 g, 96%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.90 (s, 1H), 9.09 (s, 1H), 8.91 (s, 1H), 8.87 (br s, 2H), 8.51 (d,J=5.2 Hz, 1H), 8.41 (s, 1H), 8.05 (dd, J=5.0, 1.3 Hz, 1H), 7.40-7.32 (m,4H), 7.29-7.23 (m, 1H), 4.09 (s, 3H), 3.88-3.83 (m, 4H), 3.78 (s, 2H),3.35-3.28 (m, 4H). MS=456 (MH)+.

Example 3722-(3-Methoxy-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide

2-(3-Methoxy-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-(3-Methoxy-phenyl)-acetamide (43.0 mg, 0.260 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.056 g, 42%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 10.87 (s, 1H), 9.09 (s, 1H), 8.91 (s, 1H),8.87 (br s, 2H), 8.51 (dd, J=5.1, 0.6 Hz, 1H), 8.41 (s, 1H), 8.05 (dd,J=5.1, 1.4 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 6.97-6.93 (m, 2H), 6.86-6.82(m, 1H), 4.09 (s, 3H), 3.88-3.83 (m, 4H), 3.78 (s, 3H), 3.74 (s, 2H),3.35-3.29 (m, 4H). MS=486 (MH)+.

Example 373N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-(3-trifluoromethyl-phenyl)-acetamide

373a) 2-(3-Trifluoromethyl-phenyl)-acetamide was prepared from(3-Trifluoromethyl-phenyl)-acetic acid (1.0 g, 4.9 mmol) in an analogousmanner to Example 313a. Product isolated as white solid (0.88 g, 88%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 7.63-7.51 (m, 5H), 6.96 (br s, 1H),3.50 (s, 2H). MS=204 (MH)+.

373b)N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-(3-trifluoromethyl-phenyl)-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-(3-Trifluoromethyl-phenyl)-acetamide (53.0 mg, 0.261 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe trifluoroacetic acid salt as a yellow lyophilate (0.037 g, 26%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.98 (s, 1H), 9.07 (s, 1H), 8.91 (s,1H), 8.87 (br s, 2H), 8.52 (dd, J=5.1, 0.4 Hz, 1H), 8.41 (s, 1H), 8.06(dd, J=5.1, 1.4 Hz, 1H), 7.75 (s, 1H), 7.70-7.57 (m, 3H), 4.09 (s, 3H),3.92 (s, 2H), 3.88-3.83 (m, 4H), 3.35-3.28 (m, 4H). MS=524 (MH)+.

Example 3742-(4-Methoxy-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide

2-(4-Methoxy-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and4-Methoxyphenylacetamide (43.0 mg, 0.260 mmol) in an analogous manner toExample 303c and Example 1501c. Product isolated as the trifluoroaceticacid salt as a yellow lyophilate (0.067 g, 50%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 10.83 (s, 1H), 9.08 (s, 1H), 8.91 (s, 1H), 8.85 (br s,2H), 8.50 (dd, J=5.1, 0.6 Hz, 1H), 8.41 (s, 1H), 8.04 (dd, J=5.1, 1.4Hz, 1H), 7.29 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.09 (s, 3H),3.88-3.83 (m, 4H), 3.73 (s, 3H), 3.69 (s, 2H), 3.35-3.29 (m, 4H). MS=486(MH)+.

Example 375[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-morpholin-4-yl-pyridin-3-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-morpholin-4-yl-pyridin-3-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (106.0 mg, 0.2320 mmol) and6-Morpholin-4-yl-pyridin-3-ylamine (48.0 mg, 0.268 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.148 g, 87%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.52 (br s, 1H), 8.98-8.85 (m, 3H),8.59 (br s, 1H), 8.43 (s, 1H), 8.26 (d, J=5.3 Hz, 1H), 8.01-7.96 (m,1H), 7.90 (s, 1H), 7.70 (d, J=5.2 Hz, 1H), 7.09 (br s, 1H), 4.10 (s,3H), 3.90-3.85 (m, 4H), 3.77-3.72 (m, 4H), 3.48-3.42 (m, 4H), 3.36-3.29(m, 4H). MS=500 (MH)+.

Example 376{2-[2-(Pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{2-[2-(Pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (103.0 mg, 0.2413 mmol) and 3-aminopyridine (27.0mg, 0.287 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the bis-trifluoroacetic acid salt as a paleyellow lyophilate (0.141 g, 95%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.25 (br s, 1H), 9.39 (s, 1H), 9.24 (d, J=0.6 Hz, 1H), 8.97 (br s, 2H),8.76 (d, J=5.5 Hz, 1H), 8.73 (d, J=5.6 Hz, 1H), 8.51-8.45 (m, 2H), 8.38(d, J=5.2 Hz, 1H), 8.28 (dd, J=5.6, 0.7 Hz, 1H), 8.07 (s, 1H), 7.93 (dd,J=5.3, 1.2 Hz, 1H), 7.81 (dd, J=8.2, 5.34 Hz, 1H), 5.02-4.93 (m, 1H),3.78-3.69 (m, 1H), 3.55-3.34 (m, 3H), 2.47-2.37 (m, 1H), 2.32-2.22 (m,1H). MS=385 (MH)+.

Example 377{5-Methoxy-2-[2-(pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{5-Methoxy-2-[2-(pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (107.0 mg, 0.2342 mmol) and 3-aminopyridine (25.0mg, 0.266 mmol) in an analogous manner to Example 303c and Example1501c. Product Isolated as the Bis-Trifluoroacetic Acid Salt as a PaleYellow Lyophilate (0.063 g, 41%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.15 (br s, 1H), 9.31 (s, 1H), 9.05 (br s, 1H), 8.92 (br s, 1H), 8.84(s, 1H), 8.48-8.41 (m, 3H), 8.34 (d, J=5.0 Hz, 1H), 8.20 (d, J=6.3 Hz,1H), 8.03 (s, 1H), 7.87 (d, J=5.3 Hz, 1H), 7.74-7.71 (m, 1H), 5.09-5.00(m, 1H), 4.17 (s, 3H), 3.74-3.65 (m, 1H), 3.52-3.29 (m, 3H), 2.54-2.44(m, 1H), 2.27-2.17 (m, 1H). MS=415 (MH)+.

Example 378[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyridin-3-yl-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyridin-3-yl-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and 3-aminopyridine (25.0mg, 0.266 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the bis trifluoroacetic acid salt as a yellowlyophilate (0.123 g, 87%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.17 (brs, 1H), 9.33 (s, 1H), 9.02-8.88 (m, 3H), 8.49-8.42 (m, 3H), 8.34 (d,J=4.6 Hz, 1H), 8.03 (s, 1H), 7.87 (dd, J=5.2, 1.3 Hz, 1H), 7.74 (dd,J=8.3, 5.2 Hz, 1H), 4.11 (s, 3H), 3.92-3.86 (m, 4H), 3.37-3.30 (m, 4H).MS=415 (MH)+.

Example 3792-[4-(5-Methoxy-4-piperazin-1-yl-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinamide

2-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-Amino-isonicotinamide (36.0 mg, 0.262 mmol) in an analogous manner toExample 303c and Example 1501c. Product isolated as the trifluoroaceticacid salt as a yellow lyophilate (0.004 g, 2%). ¹HNMR (400 MHz, d6-DMSO,δ, ppm): 8.94 (s, 1H), 8.86 (br s, 2H), 8.69 (s, 1H), 8.46 (d, J=5.5 Hz,1H), 8.44 (s, 1H), 8.41 (d, J=5.3 Hz, 1H), 8.19 (br s, 1H), 8.09 (br s,1H), 7.95-7.91 (m, 1H), 7.71 (br s, 1H), 7.36-7.33 (m, 1H), 4.11 (s,3H), 3.93-3.89 (m, 4H), 3.37-3.30 (m, 4H). MS=458 (MH)+.

Example 3806-[4-(5-Methoxy-4-piperazin-1-yl-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-nicotinamide

6-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-nicotinamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and 6-Amino-nicotinamide(36.0 mg, 0.262 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the trifluoroacetic acid salt as a paleyellow lyophilate (0.047 g, 37%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.08(br s, 2H), 8.94 (s, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 8.50 (d, J=5.4 Hz,1H), 8.45 (s, 1H), 8.26 (br s, 1H), 8.10-7.99 (m, 2H), 7.72 (br s, 1H),7.47 (br s, 1H), 4.11 (s, 3H), 3.96-3.92 (m, 4H), 3.36-3.29 (m, 4H).MS=458 (MH)+.

Example 382(3-Methoxy-4-morpholin-4-yl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(3-Methoxy-4-morpholin-4-yl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (110.0 mg, 0.2407 mmol) and3-Methoxy-4-morpholin-4-yl-phenylamine (55.0 mg, 0.264 mmol) [preparedas described in WO2008/051547] in an analogous manner to Example 303cand Example 1501c. Product isolated as the trifluoroacetic acid salt asan orange lyophilate (0.147 g, 95%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):9.71 (br s, 1H), 9.12-8.95 (m, 2H), 8.91 (s, 1H), 8.43 (s, 1H), 8.25 (d,J=5.3 Hz, 1H), 7.99 (s, 1H), 7.72 (d, J=4.9 Hz, 1H), 7.44 (br s, 1H),7.25 (d, J=7.5 Hz, 1H), 7.06 (br s, 1H), 4.11 (s, 3H), 3.92-3.86 (m,4H), 3.84 (s, 3H), 3.82-3.76 (m, 4H), 3.35-3.29 (m, 4H), 3.17-3.00 (m,4H). MS=529 (MH)+.

Example 383[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-methyl-4-morpholin-4-yl-phenyl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-methyl-4-morpholin-4-yl-phenyl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-Methyl-4-morpholin-4-yl-phenylamine (50.0 mg, 0.260 mmol)[prepared asdescribed in WO2008/051547] in an analogous manner to Example 303c andExample 1501c. Product isolated as the trifluoroacetic acid salt as anorange lyophilate (0.125 g, 91%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.06 (br s, 1H), 9.07-8.95 (m, 2H), 8.92 (s, 1H), 8.46 (s, 1H), 8.01(d, J=5.9 Hz, 1H), 7.74 (dd, J=6.3, 1.1 Hz, 1H), 7.27 (d, J=8.7 Hz, 1H),7.00 (d, J=2.5 Hz, 1H), 6.92 (dd, J=8.8, 2.7 Hz, 1H), 4.11 (s, 3H),3.89-3.84 (m, 4H), 3.79-3.75 (m, 4H), 3.34-3.27 (m, 4H), 3.20-3.16 (m,4H), 2.20 (s, 3H). MS=513 (MH)+.

Example 3845-[4-(5-Methoxy-4-piperazin-1-yl-y-2-y-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-pyridine-2-carbonitrile

5-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-yl-pyridpyridin-2-ylamino]-pyridine-2-carbonitrilewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and5-Amino-pyridine-2-carbonitrile (32.0 mg, 0.269 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.093 g, 76%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 10.24 (s, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.91(s, 1H), 8.88 (br s, 2H), 8.56 (dd, J=8.7, 2.6 Hz, 1H), 8.47 (d, J=5.4Hz, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.90 (dd,J=5.4, 1.4 Hz, 1H), 4.11 (s, 3H), 3.91-3.87 (m, 4H), 3.36-3.30 (m, 4H).MS=440 (MH)+.

Example 385{5-Methoxy-2-[2-(pyrimidin-5-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine

{5-Methoxy-2-[2-(pyrimidin-5-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-aminewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (108.0 mg, 0.2364 mmol) and Pyrimidin-5-ylamine(25.0 mg, 0.263 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the trifluoroacetic acid salt as a yellowlyophilate (0.029 g, 22%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.77 (s,1H), 9.22-9.21 (m, 2H), 9.00-8.80 (m, 3H), 8.74 (s, 1H), 8.43-8.40 (m,2H), 8.18 (d, J=6.3 Hz, 1H), 7.99 (s, 1H), 7.83 (dd, J=5.3, 1.4 Hz, 1H),5.08-4.98 (m, 1H), 4.17 (s, 3H), 3.74-3.64 (m, 1H), 3.50-3.30 (m, 3H),2.52-2.44 (m, 1H), 2.28-2.18 (m, 1H). MS=416 (MH)+.

Example 386[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrimidin-5-yl-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrimidin-5-yl-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and Pyrimidin-5-ylamine(25.0 mg, 0.263 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the trifluoroacetic acid salt as a yellowlyophilate (0.073 g, 62%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.79 (s,1H), 9.22-9.21 (m, 2H), 8.98-8.95 (m, 3H), 8.74 (s, 1H), 8.43-8.40 (m,2H), 7.99 (s, 1H), 7.82 (dd, J=5.3, 1.4 Hz, 1H), 4.11 (s, 3H), 3.92-3.86(m, 4H), 3.37-3.29 (m, 4H).

MS=416 (MH)+.

Example 387[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyridin-2-yl-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyridin-2-yl-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (102.0 mg, 0.2232 mmol) and 2-Pyridinamine (25.0mg, 0.266 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the trifluoroacetic acid salt as a yellowlyophilate (0.056 g, 47%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 11.54 (brs, 1H), 9.05-8.90 (m, 3H), 8.53 (d, J=4.9 Hz, 1H), 8.50-8.45 (m, 2H),8.39 (d, J=5.2 Hz, 1H), 8.11-8.00 (m, 2H), 7.54 (s, 1H), 7.21 (s, 1H),4.12 (s, 3H), 3.94-3.89 (m, 4H), 3.37-3.30 (m, 4H). MS=415 (MH)+.

Example 3882-[4-(5-Methoxy-4-morpholin-4-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinonitrile

388a)2-(2-Chloro-pyridin-4-yl)-5-methoxy-4-morpholin-4-yl-pyrido[3,4-d]pyrimidinewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (0.25 g,0.86 mmol) and Morpholine (0.10 mL, 1.1 mmol) in an analogous manner to[B016]. Product isolated as a tan solid (0.269 g, 87%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 8.87 (s, 1H), 8.60 (dd, J=5.0, 0.9 Hz, 1H), 8.38 (s,1H), 8.33-8.30 (m, 2H), 4.08 (s, 3H), 3.81-3.71 (m, 8H). MS=358 (MH)+.388b)2-[4-(5-Methoxy-4-morpholin-4-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinonitrilewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-4-morpholin-4-yl-pyrido[3,4-d]pyrimidine(100.0 mg, 0.2795 mmol) and 2-Amino-isonicotinonitrile (40.0 mg, 0.336mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.014g, 9%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.63 (br s, 1H), 8.87 (s,1H), 8.58 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H), 8.37(s, 1H), 8.29 (s, 1H), 7.92 (d, J=5.4 Hz, 1H), 7.35 (d, J=4.9 Hz, 1H),4.09 (s, 3H), 3.82-3.74 (m, 8H). MS=441 (MH)+.

Example 3892-(3-Cyano-phenyl)-N-[4-(5-methoxy-4-morpholin-4-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide

2-(3-Cyano-phenyl)-N-[4-(5-methoxy-4-morpholin-4-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamidewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-4-morpholin-4-yl-pyrido[3,4-d]pyrimidine(110.0 mg, 0.3074 mmol) and 2-(3-Cyano-phenyl)-acetamide (54.0 mg, 0.337mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.082g, 44%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.96 (s, 1H), 9.03 (s, 1H),8.85 (s, 1H), 8.49 (dd, J=5.1, 0.6 Hz, 1H), 8.35 (s, 1H), 8.04 (dd,J=5.1, 1.5 Hz, 1H), 7.84-7.82 (m, 1H), 7.77-7.74 (m, 1H), 7.73-7.70 (m,1H), 7.57 (t, J=7.8 Hz, 1H), 4.07 (s, 3H), 3.89 (s, 2H), 3.79-3.69 (m,8H). MS=482 (MH)+.

Example 390[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine

4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,4,5-trimethoxy-phenyl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (106.0 mg, 0.2320 mmol) and3,4,5-Trimethoxyaniline (48.0 mg, 0.262 mmol) in an analogous manner toExample 303c and Example 1501c. Product isolated as the trifluoroaceticacid salt as an orange lyophilate (0.074 g, 52%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 9.45 (br s, 1H), 8.98-8.84 (m, 3H), 8.42 (s, 1H), 8.30(d, J=5.4 Hz, 1H), 7.94 (s, 1H), 7.70 (d, J=5.6 Hz, 1H), 7.13-7.10 (m,2H), 4.10 (s, 3H), 3.90-3.85 (m, 4H), 3.79 (s, 6H), 3.64 (s, 3H),3.36-3.29 (m, 4H). MS=504 (MH)+.

Example 391N-[4-(5-Methoxy-4-piperazin-1-yl-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-(4-trifluoromethyl-phenyl)-acetamide

391a) 2-(4-Trifluoromethyl-phenyl)-acetamide was prepared from(4-Trifluoromethyl-phenyl)-acetic acid (1.0 g, 4.9 mmol) in an analogousmanner to Example 313a. Product isolated as a white solid (0.92 g, 92%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 7.66 (d, J=8.1 Hz, 2H), 7.54 (br s,1H), 7.47 (d, J=8.0 Hz, 2H), 6.96 (br s, 1H), 3.49 (s, 2H). MS=204(MH)+.391b)N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-(4-trifluoromethyl-phenyl)-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-(4-Trifluoromethyl-phenyl)-acetamide (54.0 mg, 0.266 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe trifluoroacetic acid salt as a yellow lyophilate (0.051 g, 36%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.99 (s, 1H), 9.08 (s, 1H), 8.91 (s,1H), 8.84 (br s, 2H), 8.52 (dd, J=5.1, 0.5 Hz, 1H), 8.41 (s, 1H), 8.06(dd, J=5.1, 1.4 Hz, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H),4.09 (s, 3H), 3.92 (s, 2H), 3.87-3.83 (m, 4H), 3.34-3.28 (m, 4H). MS=524(MH)+.

Example 392[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-phenyl-pyridin-3-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-phenyl-pyridin-3-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and6-Phenyl-pyridin-3-ylamine (45.0 mg, 0.264 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.086 g, 65%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.82 (s, 1H), 9.01 (d, J=2.3 Hz, 1H),8.95-8.85 (m, 3H), 8.46-8.40 (m, 3H), 8.06-7.95 (m, 4H), 7.80 (dd,J=5.3, 1.3 Hz, 1H), 7.49 (t, J=7.4 Hz, 2H), 7.42-7.37 (m, 1H), 4.11 (s,3H), 3.92-3.87 (m, 4H), 3.37-3.30 (m, 4H). MS=491 (MH)+.

Example 393[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and6-Methyl-pyridin-3-ylamine (29.0 mg, 0.268 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.068 g, 56%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 10.22 (s, 1H), 9.34 (s, 1H), 8.96 (br s,2H), 8.91 (s, 1H), 8.46 (d, J=5.4 Hz, 1H), 8.43 (s, 1H), 8.38 (dd,J=8.8, 2.4 Hz, 1H), 8.02 (s, 1H), 7.88 (dd, J=5.3, 1.4 Hz, 1H), 7.73 (d,J=8.8 Hz, 1H), 4.11 (s, 3H), 3.91-3.87 (m, 4H), 3.36-3.30 (m, 4H), 2.61(s, 3H). MS=429 (MH)+.

Example 394[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and5-Amino-2-methoxypyridine (33.0 mg, 0.266 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as an orange lyophilate (0.091 g, 74%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.43 (s, 1H), 9.00-8.85 (m, 3H), 8.48 (d,J=2.8 Hz, 1H), 8.42 (s, 1H), 8.26 (d, J=5.4 Hz, 1H), 8.06 (dd, J=8.8,2.7 Hz, 1H), 7.89 (s, 1H), 7.69 (dd, J=5.3, 1.1 Hz, 1H), 6.83 (d, J=8.8Hz, 1H), 4.10 (s, 3H), 3.90-3.86 (m, 4H), 3.84 (s, 3H), 3.35-3.29 (m,4H). MS=445 (MH)+.

Example 395[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and6-Trifluoromethyl-pyridin-3-ylamine (43.0 mg, 0.265 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe trifluoroacetic acid salt as an orange lyophilate (0.084 g, 64%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.09 (s, 1H), 8.96 (d, J=2.5 Hz, 1H),8.94-8.84 (m, 3H), 8.61 (dd, J=8.7, 2.3 Hz, 1H), 8.46-8.42 (m, 2H), 8.04(s, 1H), 7.86 (dd, J=5.3, 1.3 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 4.11 (s,3H), 3.93-3.86 (m, 4H), 3.37-3.30 (m, 4H). MS=483 (MH)+.

Example 396N-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-2-pyridin-3-yl-acetamide

N-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-2-pyridin-3-yl-acetamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-Pyridin-3-yl-acetamide (35.0 mg, 0.257 mmol) in an analogous manner toExample 303c and Example 1501c. Product isolated as the trifluoroaceticacid salt as a yellow lyophilate (0.008 g, 6%). ¹HNMR (400 MHz, d6-DMSO,δ, ppm): 10.99 (s, 1H), 9.09 (s, 1H), 8.95-8.75 (m, 3H), 8.64 (s, 1H),8.56 (d, J=4.7 Hz, 1H), 8.51 (d, J=5.1 Hz, 1H), 8.40 (s, 1H), 8.15 (d,J=6.1 Hz, 1H), 8.07 (dd, J=5.2, 1.4 Hz, 1H), 7.93 (d, J=7.7 Hz, 1H),7.54-7.48 (m, 1H), 4.98-4.90 (m, 1H), 4.15 (s, 3H), 3.49 (s, 2H),3.70-3.60 (m, 1H), 3.48-3.28 (m, 3H), 2.53-2.43 (m, 1H), 2.25-2.15 (m,1H). MS=457 (MH)+.

Example 3972-{4-[5-Methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile

397a)2-(2-Chloro-pyridin-4-yl)-5-methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidinewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (0.25 g,0.86 mmol) and 1-Methylpiperazine (0.12 mL, 1.0 mmol) in an analogousmanner to [B016]. Product isolated as tan needles (0.283 g, 88%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 8.85 (s, 1H), 8.60 (d, J=5.1 Hz, 1H), 8.37(s, 1H), 8.33-8.29 (m, 2H), 4.07 (s, 3H), 3.75-3.70 (m, 4H), 2.52-2.48(m, 4H), 2.24 (s, 3H). MS=371, 373 (MH)+. 397b)2-{4-[5-Methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrilewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine(100.0 mg, 0.2697 mmol) and 2-Amino-isonicotinonitrile (39.0 mg, 0.327mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.123g, 80%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.46 (s, 1H), 9.83 (s, 1H),8.94 (s, 1H), 8.64 (s, 1H), 8.51 (dd, J=5.0, 0.6 Hz, 1H), 8.49 (d, J=5.3Hz, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.93 (dd, J=5.3, 1.4 Hz, 1H), 7.33(dd, J=5.1, 1.4 Hz, 1H), 4.43 (d, J=13.4, 2H), 4.12 (s, 3H), 3.60 (d,J=11.8 Hz, 2H), 3.46 (t, J=12.9 Hz, 2H), 3.30-3.20 (m, 2H), 2.97-2.85(m, 3H). MS=454 (MH)+.

Example 3982-(3-Chloro-phenyl)-N-{4-[5-methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

2-(3-Chloro-phenyl)-N-{4-[5-methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine(100.0 mg, 0.2697 mmol) and 2-(3-Chloro-phenyl)-acetamide (55.1 mg,0.325 mmol) in an analogous manner to Example 303c and Example 1501c.Product isolated as the trifluoroacetic acid salt as an orangelyophilate (0.050 g, 29%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.94 (s,1H), 9.89 (br s, 1H), 9.09 (s, 1H), 8.92 (s, 1H), 8.52 (dd, J=5.1, 0.6Hz, 1H), 8.42 (s, 1H), 8.07 (dd, J=5.2, 1.5 Hz, 1H), 7.47-7.75 (m, 1H),7.41-7.32 (m, 3H), 4.37 (d, J=13.9 Hz, 2H), 4.11 (s, 3H), 3.81 (s, 2H),3.59 (d, J=11.8 Hz, 2H), 3.41 (t, J=13.1 Hz, 2H), 3.29-3.17 (m, 2H),2.89 (s, 3H). MS=504, 506 (MH)+.

Example 399N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-pyridin-3-yl-acetamide

N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-pyridin-3-yl-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-Pyridin-3-yl-acetamide (36.0 mg, 0.264 mmol), in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.115 g, 91%). HNMR(400 MHz, d6-DMSO, δ, ppm): 11.03 (s, 1H), 9.07 (s, 1H), 8.92-8.83 (m,3H), 8.71 (d, J=1.5 Hz, 1H), 8.64 (dd, J=5.1, 1.2 Hz, 1H), 8.52 (dd,J=5.1, 0.6 Hz, 1H), 8.41 (s, 1H), 8.11-8.05 (m, 2H), 7.68-7.63 (m, 1H),4.09 (s, 3H), 3.96 (s, 2H), 3.87-3.82 (m, 4H), 3.34-3.28 (m, 4H). MS=457(MH)+.

Example 400N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-pyridin-4-yl-acetamide

N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-pyridin-4-yl-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-Pyridin-4-yl-acetamide (35.0 mg, 0.257 mmol) in an analogous manner toExample 303c and Example 1501c. Product isolated as the trifluoroaceticacid salt as an orange lyophilate resin (0.113 g, 90%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 11.06 (s, 1H), 9.07 (s, 1H), 8.90 (s, 1H), 8.86 (br s,2H), 8.71 (s, 2H), 8.53 (dd, J=5.1, 0.6 Hz, 1H), 8.41 (s, 1H), 8.08 (dd.J=5.2, 1.5 Hz, 1H), 7.71 (br s, 2H), 4.09 (s, 3H), 4.03 (s, 2H),3.87-3.83 (m, 4H), 3.34-3.28 (m, 4H). MS=457 (MH)+.

Example 401[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methoxy-pyridin-2-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methoxy-pyridin-2-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and4-Methoxy-pyridin-2-ylamine (33.0 mg, 0.266 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.098 g, 79%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.00-8.90 (m, 3H), 8.55 (d, J=5.4 Hz, 1H),8.45 (s, 1H), 8.31 (s, 1H), 8.24 (d, J=6.9 Hz, 1H), 8.12-8.08 (m, 1H),6.92 (br s, 2H), 4.11 (s, 3H), 4.00 (s, 3H), 3.93-3.88 (m, 4H),3.37-3.30 (m, 4H). MS=445 (MH)+.

Example 4022-{4-[4-(4-Hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile

402a)1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-olwas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (0.40 g,1.4 mmol) and Piperidin-4-ol (0.17 g, 1.7 mmol) in an analogous mannerto [B016]. Product isolated as an orange solid (0.317 g, 62%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 8.84 (s, 1H), 8.60 (dd, J=4.9, 0.7 Hz, 1H),8.36 (s, 1H), 8.32-8.29 (m, 2H), 4.81 (d, J=4.1 Hz, 1H), 4.08 (s, 3H),4.05-3.97 (m, 2H), 3.85-3.77 (m, 1H), 3.45-3.37 (m, 2H), 1.96-1.88 (m,2H), 1.61-1.51 (m, 2H). MS=372, 374 (MH)+.

402b)2-{4-[4-(4-Hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrilewas prepared from1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol(100.0 mg, 0.2689 mmol) and 2-Amino-isonicotinonitrile (39.0 mg, 0.327mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.082g, 53%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.76 (br s, 1H), 8.84 (s,1H), 8.58 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.47 (d, J=5.6 Hz, 1H), 8.36(s, 1H), 8.23 (s, 1H), 7.93 (d, J=5.6 Hz, 1H), 7.37 (d, J=4.3 Hz, 1H),4.09 (s, 3H), 4.08-4.00 (m, 2H), 3.87-3.80 (m, 1H), 3.50-3.40 (m, 2H),1.97-1.89 (m, 2H), 1.64-1.54 (m, 2H). MS=455 (MH)+.

Example 4032-(3-Cyano-phenyl)-N-{4-[4-(4-hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

2-(3-Cyano-phenyl)-N-{4-[4-(4-hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas prepared from1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol(100.0 mg, 0.2689 mmol) and 2-(3-Cyano-phenyl)-acetamide (52.0 mg, 0.325mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.072g, 43%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.95 (s, 1H), 9.03 (s, 1H),8.82 (s, 1H), 8.49 (dd, J=5.2, 0.6 Hz, 1H), 8.34 (s, 1H), 8.03 (dd,J=5.2, 1.6 Hz, 1H), 7.84-7.82 (m, 1H), 7.77-7.74 (m, 1H), 7.73-7.70 (m,1H), 7.57 (t, J=7.8 Hz, 1H), 4.07 (s, 3H), 4.03-3.95 (m, 2H), 3.89 (s,2H), 3.85-3.77 (m, 1H), 3.45-3.36 (m, 2H), 1.94-1.86 (m, 2H), 1.60-1.50(m, 2H). MS=496 (MH)+.

Example 4042-(3-Cyano-phenyl)-N-{4-[5-methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide

2-(3-Cyano-phenyl)-N-{4-[5-methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamidewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine(100.0 mg, 0.2697 mmol) and 2-(3-Cyano-phenyl)-acetamide (52.0 mg, 0.325mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.044g, 26%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.97 (s, 1H), 9.79 (br s,1H), 9.08 (s, 1H), 8.92 (s, 1H), 8.52 (dd, J=5.1, 0.6 Hz, 1H), 8.42 (s,1H), 8.08 (dd, J=5.1, 1.5 Hz, 1H), 7.84-7.82 (m, 1H), 7.78-7.75 (m, 1H),7.73-7.70 (m, 1H), 7.58 (t, J=7.8 Hz, 1H), 4.37 (d, J=13.9 Hz, 2H), 4.11(s, 3H), 3.89 (s, 2H), 3.59 (d, J=11.0 Hz, 2H), 3.45-3.35 (m, 2H),3.28-3.18 (m, 2H), 2.91-2.87 (m, 3H). MS=495 (MH)+.

Example 405(6-Chloro-pyridin-3-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(6-Chloro-pyridin-3-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and6-Chloro-pyridin-3-ylamine (34.0 mg, 0.264 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as the free base asa yellow solid (0.010 g, 9%). MP=206-208° C. ¹HNMR (400 MHz, d6-DMSO, δ,ppm): 9.71 (s, 1H), 8.81 (s, 1H), 8.74 (d, J=2.8 Hz, 1H), 8.37-8.32 (m,3H), 7.92 (s, 1H), 7.75 (dd, J=5.4, 1.1 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H),4.07 (s, 3H), 3.68-3.63 (m, 4H), 2.90-2.85 (m, 4H). MS=449, 451 (MH)+.

Example 406(R)—N-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-2-phenyl-propionamide

406a) (R)-2-Phenyl-propionamide was prepared from (R)-2-Phenyl-propionicacid (0.941 g, 6.27 mmol) in an analogous manner to Example 313a.Product isolated as a white solid (0.457 g, 48%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 7.35 (s, 1H), 7.33-7.18 (m, 5H), 6.79 (s, 1H), 3.55(q, J=7.0 Hz, 1H), 1.30 (d, J=7.0 Hz, 3H). MS=150 (MH)+.

406b)(R)—N-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-2-phenyl-propionamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and(R)-2-Phenyl-propionamide (45.0 mg, 0.302 mmol) in an analogous mannerto Example 303c and Example 4501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.100 g, 78%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 10.79 (s, 1H), 9.12 (s, 1H), 8.97-8.77 (m,3H), 8.47 (dd, J=5.3, 0.6 Hz, 1H), 8.41 (s, 1H), 8.15 (d, J=6.0 Hz, 1H),8.03 (dd, J=5.2, 1.5 Hz, 1H), 7.47-7.43 (m, 2H), 7.37-7.32 (m, 2H),7.27-7.22 (m, 1H), 5.00-4.90 (m, 1H), 4.16 (s, 3H), 4.09 (q, J=6.9 Hz,1H), 3.72-3.62 (m, 1H), 3.50-3.30 (m, 3H), 2.53-2.47 (m, 1H), 2.27-2.17(m, 1H), 1.46 (d, J=7.0, 3H). MS=470 (MH)+.

Example 407(S)—N-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-2-phenyl-propionamide

407a) (S)-2-Phenyl-propionamide was prepared from (S)-2-Phenyl-propionicacid (1.25 g, 8.32 mmol) in an analogous manner to Example 313a. Productisolated as a white solid. ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 7.35 (s,1H), 7.33-7.18 (m, 5H), 6.79 (s, 1H), 3.55 (q, J=7.1 Hz, 1H), 1.30 (d,J=7.1 Hz, 3H).

407b)(S)—N-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-2-phenyl-propionamidewas prepared from(R)-3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and(S)-2-Phenyl-propionamide (45.0 mg, 0.302 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.100 g, 78%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 10.79 (s, 1H), 9.12 (s, 1H), 8.99-8.79 (m,3H), 8.47 (dd, J=5.2, 0.6 Hz, 1H), 8.41 (s, 1H), 8.15 (d, J=5.9 Hz, 1H),8.04 (dd, J=5.2, 1.5 Hz, 1H), 7.47-7.43 (m, 2H), 7.37-7.32 (m, 2H),7.27-7.22 (m, 1H), 5.00-4.90 (m, 1H), 4.16 (s, 3H), 4.09 (q, J=6.8 Hz,1H), 3.72-3.62 (m, 1H), 3.50-3.30 (m, 3H), 2.53-2.47 (m, 1H), 2.27-2.17(m, 1H), 1.46 (d, J=7.0 Hz, 3H). MS=470 (MH)+.

Example 408(R)—N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-phenyl-propionamide

(R)—N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-phenyl-propionamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and(R)-2-Phenyl-propionamide (45.0 mg, 0.302 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.115 g, 89%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 10.82 (s, 1H), 9.11 (s, 1H), 8.93 (s, 1H),8.88 (br s, 2H), 8.48 (dd, J=5.1, 0.7 Hz, 1H), 8.42 (s, 1H), 8.04 (dd,J=5.1, 1.4 Hz, 1H), 7.46-7.43 (m, 2H), 7.37-7.33 (m, 2H), 7.27-7.22 (m,1H), 4.12-4.05 (m, 4H), 3.90-3.86 (m, 4H), 3.36-3.29 (m, 4H), 1.45 (d,J=7.0 Hz, 3H). MS=470 (MH)+.

Example 409(S)—N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-phenyl-propionamide

(S)—N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-phenyl-propionamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and(S)-2-Phenyl-propionamide (45.0 mg, 0.302 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.104 g, 81%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 10.81 (s, 1H), 9.11 (s, 1H), 8.93 (s, 1H),8.88 (br s, 2H), 8.48 (dd, J=5.1, 0.5 Hz, 1H), 8.42 (s, 1H), 8.04 (d,J=5.1, 1.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.37-7.32 (m, 2H), 7.27-7.22 (m,1H), 4.12-4.05 (m, 4H), 3.89-3.84 (m, 4H), 3.36-3.29 (m, 4H), 1.45 (d,J=7.0 Hz, 3H). MS=470 (MH)+.

Example 410[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-methyl-pyridin-2-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-methyl-pyridin-2-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (90.0 mg, 0.197 mmol) and3-Methyl-pyridin-2-ylamine (30.0 mg, 0.277 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as the free base asa yellow foam (0.062 g, 73%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.97 (s,1H), 8.81 (s, 1H), 8.52 (s, 1H), 8.35 (dd, J=5.2, 0.5 Hz, 1H), 8.32 (s,1H), 8.15 (dd, J=4.7, 1.4 Hz, 1H), 7.80 (dd, J=5.2, 1.4 Hz, 1H),7.59-7.55 (m, 1H), 6.94 (dd, J=7.3, 5.0 Hz, 1H), 4.07 (s, 3H), 3.68-3.64(m, 4H), 2.90-2.85 (m, 4H), 2.32 (s, 3H). MS=429 (MH)+.

Example 411(3-Fluoro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(3-Fluoro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (90.0 mg, 0.197 mmol) and3-Fluoro-pyridin-2-ylamine (31.0 mg, 0.276 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.110 g, 84%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.34 (br s, 1H), 8.97-8.79 (m, 4H),8.48-8.44 (m, 2H), 8.27 (d, J=4.8 Hz, 1H), 8.04 (dd, J=5.6, 1.2 Hz, 1H),7.86-7.80 (m, 1H), 7.21-7.16 (m, 1H), 4.11 (s, 3H), 3.94-3.88 (m, 4H),3.37-3.30 (m, 4H). MS=433 (MH)+.

Example 412[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-piperazin-1-ylpyridin-3-yl)-amine

4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-piperazin-1-yl-pyridin-3-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (106 mg, 0.232 mmol) and4-(5-Amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester(73.0 mg, 0.262 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the bis-trifluoroacetic acid salt as a brownlyophilate (0.107 g, 63%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.28 (s,1H), 8.95-8.85 (m, 3H), 8.73 (br s, 2H), 8.51 (d, J=2.8 Hz, 1H), 8.42(s, 1H), 8.25 (d, J=5.4 Hz, 1H), 8.03 (dd, J=9.1, 2.8 Hz, 1H), 7.59 (s,1H), 7.66 (dd, J=5.4, 1.2 Hz, 1H), 6.97 (d, J=9.2 Hz, 1H), 4.10 (s, 3H),3.90-3.85 (m, 4H), 3.65-3.60 (m, 4H), 3.36-3.29 (m, 4H), 3.25-3.19 (m,4H). MS=499 (MH)+.

Example 413[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[2-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[2-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (102.0 mg, 0.2232 mmol) and2-Methyl-4-(4-methyl-piperazin-1-yl)-phenylamine (54.0 mg, 0.263mmol)[prepared as described in WO2008/051547] in an analogous manner toExample 303c and Example 1501c.

Product isolated as the bis-trifluoroacetic acid salt as a brownlyophilate (0.128 g, 75%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.00-9.30(m, 2H), 9.07 (br s, 2H), 8.90 (s, 1H), 8.44 (s, 1H), 8.06 (d, J=5.9 Hz,1H), 7.95 (s, 1H), 7.70 (d, J=5.7 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.02(d, J=2.3 Hz, 1H), 6.94 (dd, J=8.7, 2.4 Hz, 1H), 4.11 (s, 3H), 3.95-3.80(m, 6H), 3.55 (d, J=11.5 Hz, 2H), 3.35-3.28 (m, 4H), 3.23-3.12 (m, 2H),2.99 (t, J=13.8 Hz, 2H), 2.89 (s, 3H), 2.21 (s, 3H). MS=526 (MH)+.

Example 414[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-piperidin-4-yl-1H-pyrazol-4-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-piperidin-4-yl-1H-pyrazol-4-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and4-(4-Amino-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester(70.0 mg, 0.263 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the bis-trifluoroacetic acid salt as a brownlyophilate (0.123 g, 78%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.40 (br s,1H), 9.00 (br s, 2H), 8.90 (s, 1H), 8.75-8.65 (m, 1H), 8.50-8.37 (m,2H), 8.25 (d, J=5.6 Hz, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.62 (d, J=5.5Hz, 1H), 7.55 (s, 1H), 4.54-4.44 (m, 1H), 4.10 (s, 3H), 3.90-3.85 (m,4H), 3.47-3.40 (m, 2H), 3.36-3.30 (m, 4H), 3.15-3.02 (m, 2H), 2.23-2.06(m, 4H). MS=487 (MH)+.

Example 415[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and6-Methyl-pyridin-2-ylamine (30.0 mg, 0.277 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.095 g, 80%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 8.96-8.87 (m, 3H), 8.56 (br s, 1H), 8.53 (d,J=5.6 Hz, 1H), 8.45 (s, 1H), 8.05-8.00 (m, 1H), 7.85 (br s, 1H),7.45-7.39 (m, 1H), 7.04-6.99 (m, 1H), 4.11 (s, 3H), 3.93-3.88 (m, 4H),3.37-3.30 (m, 4H). MS=429 (MH)+.

Example 416[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methyl-pyridin-3-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methyl-pyridin-3-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (104.0 mg, 0.2276 mmol) and5-Methyl-pyridin-3-ylamine (30.0 mg, 0.277 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a pale yellow lyophilate (0.123 g, 99%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.13 (br s, 1H), 9.17 (br s, 1H),8.95-8.85 (m, 3H), 8.46 (d, J=5.4 Hz, 1H), 8.43 (s, 1H), 8.30 (s, 1H),8.24 (s, 1H), 8.02 (s, 1H), 7.87 (dd, J=5.4, 1.3 Hz, 1H), 4.11 (s, 3H),3.91-3.86 (m, 4H), 3.36-3.30 (m, 4H), 2.43 (s, 3H). MS=429 (MH)+.

Example 417(5-Chloro-pyridin-3-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(5-Chloro-pyridin-3-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and5-Chloro-pyridin-3-ylamine (35.0 mg, 0.272 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a pale yellow lyophilate (0.112 g, 90%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.88 (s, 1H), 8.91 (s, 1H), 8.84 (brs, 2H), 8.69 (d, J=2.3 Hz, 1H), 8.64 (t, J=2.2 Hz, 1H), 8.45-8.42 (m,2H), 8.13 (d, J=2.2 Hz, 1H), 7.99 (s, 1H), 7.82 (dd, J=5.3, 1.3 Hz, 1H),4.11 (s, 3H), 3.91-3.86 (m, 4H), 3.36-3.30 (m, 4H). MS=406, 408 (MH)+.

Example 418(2-Fluoro-4-morpholin-4-yl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

418a) 2-Fluoro-4-morpholin-4-yl-phenylamine was prepared from4-(3-Fluoro-4-nitro-phenyl)-morpholine (0.52 g, 2.3 mmol) [prepared asdescribed in Quan, M. L.; et. al. J. Med. Chem. 2005, 48, 1729-1744.] inan analogous manner to Example 10b. Product isolated as a pale pinksolid (0.40 g, 88%). ¹HNMR 400 MHz, d6-DMSO, δ, ppm): 6.71-6.63 (m, 2H),6.53 (dd, J=8.5, 2.3 Hz, 1H), 4.56 (br s, 2H), 3.71-3.67 (m, 4H),2.93-2.89 (m, 4H). MS=197 (MH)+.

418b)(2-Fluoro-4-morpholin-4-yl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (105.0 mg, 0.2298 mmol) and2-Fluoro-4-morpholin-4-yl-phenylamine (52.0 mg, 0.265 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe bis-trifluoroacetic acid salt as an orange lyophilate (0.120 g,70%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.27 (br s, 1H), 8.96-8.89 (m,3H), 8.43 (s, 1H), 8.16 (d, J=5.7 Hz, 1H), 7.94 (s, 1H), 7.70 (dd,J=5.6, 1.1 Hz, 1H), 7.61 (t, J=9.2 Hz, 1H), 6.93 (dd, J=14.1, 2.5 Hz,1H), 6.82 (dd, J=8.9, 2.3 Hz, 1H), 4.10 (s, 3H), 3.90-3.85 (m, 4H),3.77-3.73 (m, 4H), 3.34-3.28 (m, 4H), 3.17-3.08 (m, 4H). MS=517 (MH)+.

Example 4193-Fluoro-4-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-benzonitrile

3-Fluoro-4-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-benzonitrilewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and4-Amino-3-fluoro-benzonitrile (36.0 mg, 0.264 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as the freebase as a yellow solid (0.019 g, 19%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):9.58 (d, J=2.5 Hz, 1H), 8.91 (s, 1H), 8.85-8.70 (m, 2H), 8.45 (m, 2H),8.30 (s, 1H), 7.89 (dd, J=5.3, 1.3 Hz, 1H), 7.83 (dd, J=11.7, 1.9 Hz,1H), 7.66-7.62 (m, 1H), 4.10 (s, 3H), 3.91-3.87 (m, 4H), 3.33-3.30 (m,4H). MS=457 (MH)+.

Example 4204-Fluoro-3-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-benzonitrile

420a) A 100 mL round bottom flask equipped with a large magnetic stirbar, reflux condenser and nitrogen inlet adapter was charged with4-Fluoro-3-nitro-benzonitrile (1.0 g, 6.0 mmol), Ammonium chloride (1.6g, 30 mmol), Ethanol (20 mL, 300 mmol) and Water (10 mL, 600 mmol). Tothe suspension was added powdered Iron (1.1 g, 20 mmol). The suspensionwas stirred vigorously to allow iron to disperse into the suspensionwithout clinging to the stir bar. The mixture was kept under anatmosphere of Nitrogen. An induction period (˜20 minutes) was observedbefore the reaction began to darken to a rusty brown color and maintaina mild exotherm from 23° C. to 26° C. over the course of three hours.After 3 hours, the reaction was complete by HPLC. The reaction wasfiltered through a plug of diatomaceous earth. The filter pad was rinsedwith methanol (˜100 mL). The filtrate was evaporated to dryness. Thesolid was triturated with dichloromethane (˜100 mL) and filtered. Thefiltrate was evaporated. 3-Amino-4-fluoro-benzonitrile was isolated as abrown solid (0.78 g, 95%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 7.19 (dd,J=11.5, 8.3 Hz, 1H), 7.09 (dd, J=8.3, 2.1 Hz, 1H), 6.96 (ddd, J=8.3,4.3, 2.1 Hz, 1H), 5.69 (br s, 2H). MS=137 (MH)+.

420b)4-Fluoro-3-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-benzonitrilewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and3-Amino-4-fluoro-benzonitrile (36.0 mg, 0.264 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.096 g)

¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.41 (d, J=2.0 Hz, 1H), 8.99-8.85 (m,1H), 8.93-8.84 (m, 3H), 8.44-8.41 (m, 2H), 8.22 (s, 1H), 7.84 (dd,J=5.3, 1.4 Hz, 1H), 7.53-7.46 (m, 2H), 4.11 (s, 3H), 3.92-3.87 (m, 4H),3.36-3.30 (m, 4H). MS=457 (MH)+.

Example 421(2,6-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(2,6-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2,6-Difluoro-phenylamine (30.0 L, 0.279 mmol) in an analogous manner toExample 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.132 g, 88%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.91-8.80 (m, 4H), 8.41 (s, 1H), 8.18(d, J=5.6 Hz, 1H), 7.82 (s, 1H), 7.69-7.66 (m, 1H), 7.33-7.25 (m, 1H),7.21-7.12 (m, 2H), 4.10 (s, 3H), 3.89-3.84 (m, 4H), 3.35-3.27 (m, 4H).MS=450 (MH)+.

Example 422(2-Fluoro-6-methyl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(2-Fluoro-6-methyl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2-Fluoro-6-methyl-phenylamine (33.0 mg, 0.264 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.099 g, 67%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.98-8.83 (m, 4H), 8.42 (s, 1H), 8.14(d, J=5.5 Hz, 1H), 7.75 (br s, 1H), 7.65 (d, J=5.3 Hz, 1H), 7.26-7.10(m, 3H), 4.10 (s, 3H), 3.88-3.82 (m, 4H), 3.36-3.27 (m, 4H), 2.25 (s,3H). MS=446 (MH)+.

Example 423[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrimidin-2-yl-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrimidin-2-yl-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and 2-amino-pyrimidine(25.0 mg, 0.263 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the free base as a yellow solid (0.009 g,10%). MP=200-203° C. ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.94 (s, 1H),9.31 (s, 1H), 8.39 (s, 1H), 8.59 (d, J=4.8 Hz, 2H), 8.44-8.41 (m, 1H),8.33 (s, 1H), 7.90 (dd, J=5.2, 1.5 Hz, 1H), 7.00 (t, J=4.8 Hz, 1H), 4.07(s, 3H), 3.71-3.66 (m, 4H), 2.92-2.87 (m, 4H). MS=416 (MH)+.

Example 424[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methoxy-pyridin-3-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methoxy-pyridin-3-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (108.0 mg, 0.2364 mmol) and5-Methoxy-pyridin-3-ylamine (33.0 mg, 0.266 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.104 g, 99%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.84 (s, 1H), 8.91 (s, 1H), 8.85 (br s, 2H),8.62 (s, 1H), 8.44-8.41 (m, 2H), 8.10 (t, J=2.2 Hz, 1H), 7.99 (s, 2H),7.81 (d, J=5.3 Hz, 1H), 4.11 (s, 3H), 3.91-3.86 (m, 7H), 3.36-3.30 (m,4H). MS=445 (MH)+.

Example 425(S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-3-ol

425a)(S)-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-3-olwas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1000.0mg, 3.4639 mmol) and (S)-Piperidin-3-ol; hydrochloride (570.0 mg, 4.142mmol) in an analogous manner to [B016]. Product isolated as a yellowfoam (0.747 g, 58%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.83 (s, 1H),8.60 (dd, J=5.0, 0.6 Hz, 1H), 8.35 (s, 1H), 8.32-8.29 (m, 2H), 4.88 (d,J=3.9 Hz, 1H), 4.14-4.05 (m, 4H), 3.95-3.89 (m, 1H), 3.69-3.61 (m, 1H),3.48-3.38 (m, 1H), 3.09 (dd, J=12.4, 8.3 Hz, 1H), 1.96-1.84 (m, 2H),1.62-1.40 (m, 2H). MS=372, 374 (MH)+. 425b)(S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-3-olwas prepared from(S)-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-3-ol(101.0 mg, 0.2716 mmol) and Aniline (30.0 L, 0.329 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.102 g, 69%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.60 (br s, 1H), 8.81 (s, 1H), 8.35 (s, 1H),8.27 (d, J=5.6 Hz, 1H), 7.94 (s, 1H), 7.72-7.68 (m, 3H), 7.33 (t, J=7.7Hz, 2H), 6.99 (t, J=6.8 Hz, 1H), 4.11-4.04 (m, 5H), 3.97-3.90 (m, 1H),3.70-3.62 (m, 1H), 3.49-3.40 (m, 1H), 3.11 (dd, J=12.8, 8.3 Hz, 1H),1.98-1.85 (m, 2H), 1.65-1.43 (m, 2H). MS=429 (MH)+.

Example 4262-{4-[4-((S)-3-Hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile

2-{4-[4-((S)-3-Hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrilewas prepared from(S)-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-3-ol(109.0 mg, 0.2932 mmol) and 2-Amino-isonicotinonitrile (39.0 mg, 0.327mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.121g, 72%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.60 (br s, 1H), 8.83 (s,1H), 8.61 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.46 (d, J=5.4 Hz, 1H), 8.35(s, 1H), 8.26 (s, 1H), 7.91 (d, J=5.1 Hz, 1H), 7.34 (d, J=4.9 Hz, 1H),4.15-4.05 (m, 5H), 4.00-3.92 (m, 1H), 3.70-3.62 (m, 1H), 3.52-3.40 (m,1H), 3.11 (dd, J=12.7, 8.3 Hz, 1H), 1.98-1.87 (m, 2H), 1.67-1.43 (m,2H). MS=455 (MH)+.

Example 4271-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol

1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-olwas prepared from1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol(104.0 mg, 0.2797 mmol) and Aniline (30.0 L, 0.329 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.093 g, 61%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.66 (br s, 1H), 8.82 (s, 1H), 8.36 (s, 1H),8.25 (d, J=5.6 Hz, 1H), 7.96 (s, 1H), 7.72-7.67 (m, 3H), 7.34 (t, J=7.8Hz, 2H), 7.02 (t, J=7.2 Hz, 1H), 4.08 (s, 3H), 4.05-3.97 (m, 2H),3.87-3.79 (m, 1H), 3.47-3.39 (m, 2H), 1.96-1.88 (m, 2H), 1.63-1.52 (m,2H). MS=429 (MH)+.

Example 428(R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-3-ol

428a)(R)-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-3-olwas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1000.0mg, 3.4639 mmol) and (R)-Piperidin-3-ol; hydrochloride (570.0 mg, 4.142mmol) in an analogous manner to [B016]. Product isolated as a tan solid(0.561 g, 44%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.83 (s, 1H), 8.60(dd, J=5.0, 0.5 Hz, 1H), 8.35 (s, 1H), 8.32-8.29 (m, 2H), 4.88 (d, J=3.9Hz, 1H), 4.15-4.05 (m, 4H), 3.95-3.88 (m, 1H), 3.70-3.60 (m, 1H),3.47-3.37 (m, 1H), 3.09 (dd, J=12.7, 8.3 Hz, 1H), 1.96-1.84 (m, 2H),1.60-1.40 (m, 2H). MS=372, 374 (MH)+.

Example 4292-{4-[4-((R)-3-Hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile

2-{4-[4-((R)-3-Hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrilewas prepared from(R)-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-3-ol(105.0 mg, 0.2824 mmol) and 2-Amino-isonicotinonitrile (39.0 mg, 0.327mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.013g, 8%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.60 (br s, 1H), 8.83 (s,1H), 8.61 (s, 1H), 8.52 (d, J=5.1 Hz, 1H), 8.46 (d, J=5.7 Hz, 1H), 8.35(s, 1H), 8.26 (s, 1H), 7.91 (d, J=5.4 Hz, 1H), 7.34 (d, J=5.3 Hz, 1H),4.14-4.04 (m, 4H), 4.00-3.92 (m, 1H), 3.70-3.62 (m, 1H), 3.51-3.41 (m,1H), 3.12 (dd, J=12.9, 8.2 Hz, 1H), 1.98-1.88 (m, 2H), 1.65-1.43 (m,2H). MS=455 (MH)+.

Example 430[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(S)-1-pyrrolidin-2-ylmethyl-amine

430a)(S)-2-{[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-methyl}-pyrrolidine-1-carboxylicacid tert-butyl ester was prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1000.0mg, 3.4639 mmol) and (S)-2-Aminomethyl-pyrrolidine-1-carboxylic acidtert-butyl ester (840.0 mg, 4.194 mmol) in an analogous manner to[B016]. Product isolated as a yellow foam (0.817 g, 50%). ¹HNMR (400MHz, d6-DMSO, δ, ppm): 8.87-8.25 (m, 6H), 4.30-4.22 (m, 1H), 4.14 (s,3H), 4.01-3.91 (m, 1H), 3.72-3.50 (m, 1H), 3.37-3.27 (m, 1H), 2.03-1.78(m, 5H), 1.45-1.10 (m, 9H). MS=471, 473 (MH)+. 430b)[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(S)-1-pyrrolidin-2-ylmethyl-aminewas prepared from(S)-2-{[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-methyl}-pyrrolidine-1-carboxylicacid tert-butyl ester (108.0 mg, 0.2293 mmol) and Aniline (25.0 L, 0.274mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.109g, 87%).

¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.42 (br s, 1H), 8.97 (br s, 1H), 8.82(s, 1H), 8.64 (t, J=5.7 Hz, 1H), 8.54 (br s, 1H), 8.40 (s, 1H), 8.31 (d,J=5.4 Hz, 1H), 7.94 (s, 1H), 7.75-7.70 (m, 3H), 7.31 (t, J=7.7 Hz, 2H),6.95 (t, J=7.4 Hz, 1H), 4.15 (s, 3H), 4.12-3.85 (m, 3H), 3.34-3.14 (m,2H), 2.20-1.74 (m, 4H). MS=428 (MH)+.

Example 431[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-1-pyrrolidin-2-ylmethyl-amine

431a)(R)-2-{[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-methyl}-pyrrolidine-1-carboxylicacid tert-butyl ester was prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1000.0mg, 3.4639 mmol) and (R)-2-Aminomethyl-pyrrolidine-1-carboxylic acidtert-butyl ester (840.0 mg, 4.194 mmol) in an analogous manner to[B016]. Product isolated as a yellow foam (0.869 g, 53%). ¹HNMR (400MHz, d6-DMSO, δ, ppm): 8.86-8.25 (m, 6H), 4.31-4.21 (m, 1H), 4.14 (s,3H), 4.00-3.90 (m, 1H), 3.72-3.50 (m, 1H), 3.36-3.28 (m, 1H), 2.02-1.78(m, 5H), 1.45-1.10 (m, 9H). LC/MS=471, 473 (MH)+. 431b)[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-1-pyrrolidin-2-ylmethyl-aminewas prepared from(R)-2-{[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-methyl}-pyrrolidine-1-carboxylicacid tert-butyl ester (105.0 mg, 0.2230 mmol) and Aniline (25.0 L, 0.274mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.117g, 97%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.42 (br s, 1H), 8.97 (br s,1H), 8.82 (s, 1H), 8.64 (t, J=5.9 Hz, 1H), 8.53 (br s, 1H), 8.40 (s,1H), 8.31 (d, J=5.4 Hz, 1H), 7.94 (s, 1H), 7.75-7.70 (m, 3H), 7.31 (t,J=7.5 Hz, 2H), 6.95 (t, J=7.4 Hz, 1H), 4.15 (s, 3H), 4.12-3.85 (m, 3H),3.34-3.15 (m, 2H), 2.20-1.74 (m, 4H). MS=428 (MH)+.

Example 4322-{4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-1-yl}-ethanol

432a)2-{4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-1-yl}-ethanolwas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1000.0mg, 3.4639 mmol) and 2-Piperazin-1-yl-ethanol (550.0 mg, 4.225 mmol) inan analogous manner to Example 303c and Example 1501c. Product isolatedas a yellow solid (0.414 g, 30%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.84(s, 1H), 8.60 (dd, J=5.1, 0.7 Hz, 1H), 8.36 (s, 1H), 8.32-8.29 (m, 2H),4.46 (t, J=5.4 Hz, 1H), 4.07 (s, 3H), 3.75-3.70 (m, 4H), 3.58-3.52 (m,2H), 2.63-2.58 (m, 4H), 2.46 (t, J=6.2 Hz, 2H). LC/MS=401, 403 (MH)+.

Example 433{1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-azetidin-3-yl}-methanol

433a){1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-azetidin-3-yl}-methanolwas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1000.0mg, 3.4639 mmol) and Azetidin-3-yl-methanol; hydrochloride (550.0 mg,4.450 mmol) in an analogous manner to [B016]. Product isolated as a tansolid (0.925 g, 75%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.80 (s, 1H),8.59 (dd, J=4.8, 1.1 Hz, 1H), 8.33-8.29 (m, 3H), 4.83 (t. J=5.5 Hz, 1H),4.60-4.53 (m, 1H), 4.41-4.34 (m, 1H), 4.27-4.21 (m, 1H), 4.16-4.10 (m,1H), 4.06 (s, 3H), 3.59 (t, J=5.7 Hz, 2H), 2.85-2.75 (m, 1H). MS=358,360 (MH)+.

433b){1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-azetidin-3-yl}-methanolwas prepared from{1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-azetidin-3-yl}-methanol(114.0 mg, 0.3186 mmol) and Aniline (31.0 L, 0.340 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.117 g, 69%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.65 (br s, 1H), 8.79 (s, 1H), 8.33 (s, 1H),8.25 (d, J=5.5 Hz, 1H), 7.97 (s, 1H), 7.72-7.67 (m, 3H), 7.34 (t, J=7.8Hz, 2H), 7.01 (t, J=7.3 Hz, 1H), 4.61-4.11 (m, 4H), 4.07 (s, 3H), 3.60(d, J=6.2 Hz, 2H), 2.87-2.76 (m, 1H). MS=415 (MH)+.

Example 434{(R)-4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-yl}-methanol

434a)(R)-4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1.00 g,3.46 mmol) and (R)-2-Hydroxymethyl-piperazine-1-carboxylic acidtert-butyl ester (0.90 g, 4.2 mmol) in an analogous manner to [B016].Product isolated as an off-white solid (1.23 g, 72%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 8.86 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 8.38 (s, 1H),8.36-8.32 (m, 2H), 4.78 (t, J=5.2 Hz, 1H), 4.48 (d, J=12.7 Hz, 1H),4.17-4.11 (m, 1H), 4.09 (s, 3H), 4.06-3.99 (m, 1H), 3.88-3.80 (m, 1H),3.47-3.35 (m, 3H), 3.29-3.21 (m, 2H), 1.42 (s, 9H). LC/MS=487, 489(MH)+.

434b){(R)-4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-yl}-methanolwas prepared from(R)-4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester (104.0 mg, 0.2136 mmol) and Aniline (23.0 L, 0.252mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the free base as a yellow foam (0.033 g, 34%). ¹HNMR (400MHz, d6-DMSO, δ, ppm): 9.31 (s, 1H), 8.81 (s, 1H), 8.33 (s, 1H), 8.30(d, J=5.3 Hz, 1H), 7.89 (s, 1H), 7.77-7.73 (m, 2H), 7.66 (dd, J=5.3, 1.3Hz, 1H), 7.30-7.25 (m, 2H), 6.92-6.87 (m, 1H), 4.71 (t, J=5.5 Hz, 1H),4.24-4.15 (m, 2H), 4.07 (s, 3H), 3.44-3.36 (m, 2H), 3.16-3.02 (m, 2H),2.88-2.78 (m, 3H). MS=444 (MH)+.

Example 435(R)-7-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-hexahydro-oxazolo[3,4-a]pyrazin-3-one

(R)-7-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-hexahydro-oxazolo[3,4-a]pyrazin-3-onewas a byproduct from Example 434. Product isolated as the free base as ayellow foam (0.023 g, 23%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.31 (s,1H), 8.87 (s, 1H), 8.38 (s, 1H), 8.32 (d, J=5.2 Hz, 1H), 7.91 (s, 1H),7.77-7.74 (m, 2H), 7.69 (dd, J=5.3, 1.4 Hz, 1H), 7.31-7.26 (m, 2H),6.93-6.88 (m, 1H), 4.50-4.39 (m, 2H), 4.29 (d, J=13.1 Hz, 1H), 4.12-4.03(m, 6H), 3.77 (dd, J=13.2, 2.1 Hz, 1H), 3.17-3.06 (m, 2H). MS=470 (MH)+.

Example 436(±)-cis-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol

436a) To a solution of 3,6-Dihydro-2H-pyridine-1-carboxylic acid benzylester (1.16 g, 5.34 mmol) [prepared as described in Solares, F. L.; et.al. Tetrahedron 2006, 62, 3284-3291] in Acetone (4 mL,) and Water (4mL,) was added N-Methylmorpholine N-oxide (0.88 g, 7.5 mmol) followed by2.5 wt % (w/v) OsO4 in t-BuOH(2.5:97.5, Osmium tetraoxide:tert-Butylalcohol, 0.8 mL, 0.06 mmol). The mixture was stirred at room temperaturefor 1 hour. Reaction was complete by LC/MS. Saturated aqueous sodiumthiosulfate (50 mL) was added and mixture was stirred for 5 minutes thenextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over sodium sulfate, filtered and evaporated to a red-brown oil.The recovered oil was purified via chromatography using an ISCOapparatus (silica gel column (24 g) and 2:1 Ethyl Acetate:Hexane).(±)-cis-3,4-Dihydroxy-piperidine-1-carboxylic acid benzyl ester wasisolated as a pale yellow oil (1.13 g, 84%). ¹HNMR (400 MHz, d6-DMSO, δ,ppm): 7.43-7.27 (m, 5H), 5.05 (s, 2H), 4.66 (d, J=4.1 Hz, 1H), 4.55 (d,J=3.7 Hz, 1H), 3.75-3.64 (m, 1H), 3.51-3.18 (m, 5H), 1.69-1.60 (m, 1H),1.52-1.43 (m, 1H). MS=274 (M+Na)+.

436b) A Paar bottle (500 mL) was charged with 10% Palladium on Carbon(50% Wet)(5:45:50, Palladium:carbon black:Water, 1.0 g, 0.47 mmol)followed by a solution of (±)-cis-3,4-Dihydroxy-piperidine-1-carboxylicacid benzyl ester (1.13 g, 4.50 mmol) in 2:1 Ethyl Acetate:Methanol (50mL). The reaction mixture was degassed and charged with Hydrogen (50psi). The mixture was shaken on a Paar apparatus for 4 hours. Thereaction mixture was degassed and kept under an atmosphere of Nitrogen.The mixture was filtered through a plug of diatomaceous earth and rinsedwith dichloromethane. The filtrate was evaporated.(±)-cis-Piperidine-3,4-diol was isolated as a pale yellow oil (0.569 g,100%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 4.11 (br s, 3H), 3.57-3.53 (m,1H), 3.46-3.42 (m, 1H), 2.79-2.67 (m, 2H), 2.57-2.49 (m, 1H), 2.47-2.37(m, 1H), 1.61-1.51 (m, 1H), 1.47-1.39 (m, 1H). MS=118 (MH)+.

436c)(±)-cis-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolwas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1.00 g,3.46 mmol) and (±)-cis-Piperidine-3,4-diol (0.56 g, 4.8 mmol) inanalogous manner to [B016]. Product isolated as a pale yellow solid(0.927 g, 69%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 8.82 (s, 1H), 8.60 (dd,J=5.0, 0.5 Hz, 1H), 8.35 (s, 1H), 8.32-8.29 (m, 2H), 4.65-4.61 (m, 2H),4.07 (s, 3H), 3.94 (br s, 1H), 3.83-3.74 (m, 2H), 3.65-3.53 (m, 3H),1.94-1.85 (m, 1H), 1.73-1.65 (m, 1H). MS=388, 390 (MH)+.

436d)(1)-cis-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolwas prepared from(1)-cis-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol(100.0 mg, 0.2578 mmol) and Aniline (29.0 μL, 0.318 mmol) in ananalogous manner to Example 303c. Product isolated as the free base as ayellow solid (0.039 g, 34%). MP=241-243° C. ¹HNMR (400 MHz,d6-DMSO, δ,ppm): 9.32 (s, 1H), 8.79 (s, 1H), 8.32-8.29 (m, 2H), 7.90 (s, 1H),7.77-7.74 (m, 2H), 7.67 (dd, J=5.3, 1.3 Hz, 1H), 7.30-7.25 (m, 2H),6.92-6.87 (m, 1H), 4.64-4.60 (m, 2H), 4.07 (s, 3H), 3.98-3.88 (m, 1H),3.85-3.72 (m, 2H), 3.66-3.53 (m, 3H), 1.97-1.87 (m, 1H), 1.76-1.66 (m,1H). MS=445 (MH)+.

Example 437(±)-trans-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol

437a) (±)-trans-Piperidine-3,4-diol was prepared from(1)-trans-3,4-Dihydroxy-piperidine-1-carboxylic acid benzyl ester (1.0g, 4.0 mmol) [prepared as described in Solares, F. L.; et. al.Tetrahedron 2006, 62, 3284-3291] in an analogous manner to Example 436a.Product isolated as a pale yellow oil (0.451 g, 97%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 4.59 (br s, 2H), 4.09 (br s, 1H), 3.20-3.13 (m, 1H),3.11-3.04 (m, 1H), 2.88 (ddd, J=4.4, 12.1, 1.2 Hz, 1H), 2.77 (dddd,J=12.6, 4.1, 4.1, 1.2 Hz, 1H), 2.35 (dddd, J=14.1, 11.3, 2.9 Hz, 1H),2.15 (dd, J=12.2, 9.1 Hz, 1H), 1.71 (dddd, J=12.6, 3.8, 3.8, 3.8 Hz,1H), 1.25-1.15 (m, 1H). MS=118 (MH)+. 437b)(±)-trans-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolwas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1.00 g,3.46 mmol) and (±)-trans-Piperidine-3,4-diol (0.46 g, 3.9 mmol) in ananalogous manner to [B016]. Product isolated as a tan solid (0.700 g,52%). MP=213-216° C. ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.83 (s, 1H),8.61 (dd, J=5.0, 0.6 Hz, 1H), 8.36 (s, 1H), 8.32-8.29 (m, 2H), 5.00 (d,J=4.1 Hz, 1H), 4.94 (d, J=4.2 Hz, 1H), 4.11-4.03 (m, 4H), 4.00-3.90 (m,1H), 3.59-3.47 (m, 2H), 3.44-3.37 (m, 1H), 3.16 (dd, J=13.1, 7.9 Hz,1H), 2.07-1.99 (m, 1H), 1.54-1.44 (m, 1H). MS=388, 390 (MH)+.

437c) desired(1)-trans-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolwas prepared from(±)-trans-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol(100.0 mg, 0.2578 mmol) and Aniline (29.0 μL, 0.318 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe free base as tan foam (0.1126 g, 98%). ¹HNMR (400 MHz, d6-DMSO, δ,ppm): 9.32 (s, 1H), 8.80 (s, 1H), 8.33 (s, 1H), 8.30 (d, J=5.4 Hz, 1H),7.90 (s, 1H), 7.77-7.74 (m, 2H), 7.67 (dd, J=5.3, 1.3 Hz, 1H), 7.40-7.36(m, 1H), 7.30-7.25 (m, 2H), 6.92-6.87 (m, 1H), 5.00 (d, J=4.1 Hz, 1H),4.94 (d, J=4.2 Hz, 1H), 4.10-4.04 (m, 4H), 3.98 (d, J=13.4 Hz, 1H),3.55-3.46 (m, 1H), 3.40 (dddd, J=7.7, 7.7, 4.2, 4.2 Hz, 1H), 3.13 (dd,J=13.0, 7.7 Hz, 1H), 2.09-2.00 (m, 1H), 1.57-1.46 (m, 1H). MS=445 (MH)+.

Example 4384-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-one

438a)4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-onewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1.0 g,3.5 mmol) and Piperazin-2-one (0.42 g, 4.2 mmol) in an analogous mannerto [B016]. Product isolated as a tan solid (1.12 g, 87%). ¹HNMR (400MHz, d6-DMSO, δ, ppm): 8.89 (s, 1H), 8.63-8.60 (m, 1H), 8.41 (s, 1H),8.34-8.32 (m, 2H), 8.15 (s, 1H), 4.23 (s, 2H), 4.10 (s, 3H), 3.95-3.90(m, 2H), 3.43-3.39 (m, 2H). LC/MS=371, 373 (MH)+.

438b)4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-onewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-one(100.0 mg, 0.2697 mmol) and Aniline (30.0 L, 0.329 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.022 g, 19%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.66 (br s, 1H), 8.87 (s, 1H), 8.40 (s, 1H),8.27 (d, J=5.5 Hz, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.74-7.69 (m, 3H),7.34 (t, J=7.7 Hz, 2H), 7.00 (t, J=7.0 Hz, 1H), 4.23 (s, 2H), 4.10 (s,3H), 3.92-3.87 (m, 2H), 3.46-3.41 (m, 2H). MS=428 (MH)+.

Example 439(2,3-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(2,3-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2,3-Difluoro-phenylamine (27.0 L, 0.266 mmol) in an analogous manner toExample 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.125 g, 84%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.24 (s, 1H), 8.91 (s, 1H), 8.86 (brs, 2H), 8.42 (s, 1H), 8.33 (d, J=5.4 Hz, 1H), 8.10 (s, 1H), 8.07-8.03(m, 1H), 7.78 (dd, J=5.3, 1.4 Hz, 1H), 7.19-7.11 (m, 1H), 7.06-6.98 (m,1H), 4.10 (s, 3H), 3.91-3.86 (m, 4H), 3.36-3.29 (m, 4H). MS=450 (MH)+.

Example 440(2,5-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(2,5-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2,5-Difluoro-phenylamine (27.0 L, 0.268 mmol) in an analogous manner toExample 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.036 g, 24%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.25 (s, 1H), 8.91 (s, 1H), 8.89 (brs, 2H), 8.45-8.38 (m, 3H), 8.21 (s, 1H), 7.81 (dd, J=5.3, 1.4 Hz, 1H),7.31-7.24 (m, 1H), 6.80-6.74 (m, 1H), 4.11 (s, 3H), 3.92-3.87 (m, 4H),3.36-3.30 (m, 4H). MS=450 (MH)+.

Example 441[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4,6-trifluoro-phenyl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4,6-trifluoro-phenyl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2,4,6-Trifluoro-phenylamine (39.0 mg, 0.265 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.092 g, 60%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.93 (br s, 2H), 8.90 (s, 1H), 8.82(s, 1H), 8.42 (s, 1H), 8.17 (dd, J=5.4, 0.5 Hz, 1H), 7.83 (s, 1H), 7.68(dd, J=5.3, 1.4 Hz, 1H), 7.34-7.23 (m, 2H), 4.10 (s, 3H), 3.90-3.84 (m,4H), 3.35-3.29 (m, 4H). MS=468 (MH)+.

Example 442((R)-4-{2-[2-(2,6-Difluoro-phenylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-piperazin-2-yl)-methanol

((R)-4-{2-[2-(2,6-Difluoro-phenylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-piperazin-2-yl)-methanolwas prepared from(R)-4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2054 mmol) and2,6-Difluoro-phenylamine (32.0 mg, 0.248 mmol) in an analogous manner toExample 303c and Example 1501c. Product isolated as the free base as atan foam (0.066 g, 66%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.80 (s, 1H),8.76 (s, 1H), 8.32 (s, 1H), 8.15 (d, J=5.3 Hz, 1H), 7.77 (s, 1H), 7.64(d, J-5.2, 1.3 Hz, 1H), 7.31-7.10 (m, 3H), 4.70 (t, J=5.5 Hz, 1H),4.21-4.12 (m, 2H), 4.06 (s, 3H), 3.42-3.35 (m, 2H), 3.15-3.00 (m, 2H),2.86-2.77 (m, 3H). MS=480 (MH)+.

Example 4433-Hydroxymethyl-1-[5-methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol

443a) To a cooled solution of 4-Oxo-piperidine-3-carboxylic acid ethylester; hydrochloride (5.0 g, 24 mmol) and Sodium bicarbonate (4.40 g,52.4 mmol) in Water (50 mL) at 50C was added Benzyl chloroformate (3.40mL, 23.8 mmol) dropwise. The mixture was stirred at room temperatureovernight. Saturated aqueous sodium carbonate (10 mL) was added andstirred for 30 minutes. The reaction mixture was extracteddichloromethane (3×30 mL). The combined organic layer was dried overmagnesium sulfate, filtered and evaporated. The crude material waspurified via chromatography using an ISCO apparatus (silica gel column120 g and 10%-*50% Ethyl Acetate:hexane).4-Oxo-piperidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester wasisolated as a clear oil (7.30 g, 100%). ¹HNMR (400 MHz, CDCl3, δ, ppm):12.07 (s, 1H), 7.43-7.29 (m, 5H), 5.20-5.15 (m, 2H), 4.24 (q, J=7.2 Hz,2H), 4.14 (br s, 2H), 3.65 (t, J=5.9 Hz, 2H), 2.39 (br s, 2H), 1.31 (t,J=7.2 Hz, 3H). MS=328 (M+Na)+. 443b) Sodium borohydride (4.5 g, 120mmol) was added in 0.5 g portions over 1 hour to a stirred solution of4-Oxo-piperidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester (3.0g, 9.8 mmol) in Methanol (30 mL) under an atmosphere of Nitrogen at roomtemperature. Gas evolution and exotherm was noted during each addition.The slow portionwise addition kept reaction temperatures below 25° C.during the course of additions. The mixture was stirred for 1 hour atroom temperature then slowly warmed. The reaction was refluxed for 4hours, cooled to room temperature and stirred overnight. A 1:1 mixtureof water:methanol (100 mL) was added dropwise to the reaction over 1hour. No exotherm or gas evolution was noted. The mixture was stirredfor 4 hours. The methanol was evaporated under reduced pressure.Methanol (50 mL) was added and the white suspension was heated at refluxfor 30 minutes. The methanol was evaporated under reduced pressure. Thiswas repeated twice. The mixture was evaporated to a white oily solid.The solid was triturated with dichloromethane (3×50 mL) and decanted.The combined organic was dried over magnesium sulfate, filtered andevaporated. 4-Hydroxy-3-hydroxymethyl-piperidine-1-carboxylic acidbenzyl ester was isolated as a clear oil (0.655 g, 25%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 7.41-7.28 (m, 5H), 5.13-5.00 (m, 2H), 4.70-4.56 (m,1H), 4.50-4.39 (m, 1H), 4.09-3.60 (m, 3H), 3.47-2.58 (m, 4H), 1.80-1.20(m, 3H). MS=288 (M+Na)+. 443c) 3-Hydroxymethyl-piperidin-4-ol wasprepared from 4-Hydroxy-3-hydroxymethyl-piperidine-1-carboxylic acidbenzyl ester (0.655 g, 2.47 mmol) in an analogous manner to Example436b. Product isolated as a viscous oil (0.324 g, 100%). ¹HNMR (400 MHz,d6-DMSO, 6, ppm): 4.60-3.18 (m, 7H), 3.3-2.78 (m, 1H), 2.70-2.56 (m,1H), 2.43-2.10 (m, 1H), 1.74-1.18 (m, 3H).

443d)1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-3-hydroxymethyl-piperidin-4-olwas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (0.70 g,2.4 mmol) and 3-Hydroxymethyl-piperidin-4-ol (0.324 g, 2.47 mmol) in ananalogous manner to [B016]. Product isolated as a pale yellow foam(0.342 g, 35%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.83 (d, J=5.4 Hz,1H), 8.61-5.85 (m, 1H), 8.35 (d, J=6.2 Hz, 1H), 8.33-8.29 (m, 2H),4.78-4.69 (m, 1H), 4.58-4.46 (m, 1H), 4.36-3.70 (m, 6H), 3.56-3.12 (m,4H), 2.02-1.45 (m, 3H). MS=402, 404 (MH)+.

443e)3-Hydroxymethyl-1-[5-methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-olwas prepared from1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-3-hydroxymethyl-piperidin-4-ol(100.0 mg, 0.2488 mmol) and Aniline (28.0 L, 0.307 mmol) in an analogousmanner to Example 303c and Example 1501c. Product was isolated as thefree base as a mixture of enantiomers as a yellow foam (0.071 g, 62%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.31 (d, J=3.0 Hz, 1H), 8.80 (d, J=4.5Hz, 1H), 8.34-8.29 (m, 2H), 7.90 (s, 1H), 7.75 (d, J=7.7 H, 2H), 7.68(dd, J=5.3, 1.2 Hz, 1H), 7.31-7.25 (m, 2H), 6.92-6.87 (m, 1H), 4.79-4.69(m, 1H), 4.55-4.43 (m, 1H), 4.30-3.70 (m, 6H), 3.56-3.25 (m, 3H),3.19-2.91 (m, 1H), 2.04-1.50 (m, 3H). MS=459 (MH)+.

Example 444[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3,6-trifluoro-phenyl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3,6-trifluoro-phenyl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (121.0 mg, 0.2648 mmol) and2,3,6-Trifluoro-phenylamine (33.9 μL, 0.320 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.155 g, 84%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.07 (s, 1H), 8.94-8.84 (m, 3H), 8.42(s, 1H), 8.21 (d, J=5.3 Hz, 1H), 7.89 (s, 1H), 7.72 (dd, J=5.3, 1.4 Hz,1H), 7.33 (dddd, J=9.7, 9.7, 9.7, 4.9 Hz, 1H), 7.21 (dddd, J=9.6, 4.7,4.7, 2.2 Hz, 1H), 4.10 (s, 3H), 3.91-3.84 (m, 4H), 3.36-3.28 (m, 4H).MS=468 (MH)+.

Example 445[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-trifluoromethyl-phenyl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-trifluoromethyl-phenyl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (124.0 mg, 0.2714 mmol) and2-(trifluoromethyl)-Benzenamine (40.0 μL, 0.318 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.134 g, 69%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.00-8.85 (m, 4H), 8.42 (d, J=2.3 Hz,1H), 8.19 (dd, J=5.4, 1.4 Hz, 1H), 7.99 (s, 1H), 7.80-7.66 (m, 4H),7.44-7.37 (m, 1H), 4.11 (s, 3H), 3.90-3.84 (m, 4H), 3.35-3.28 (m, 4H).MS=482 (MH)+.

Example 446[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-trifluoromethyl-phenyl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-trifluoromethyl-phenyl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (140.0 mg, 0.3064 mmol) and3-(trifluoromethyl)-Benzenamine (46.2 μL, 0.370 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.179 g, 98%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.76 (s, 1H), 8.93-8.83 (m, 3H), 8.42 (s,1H), 8.41 (d, J=5.4 Hz, 1H), 8.34 (s, 1H), 7.97 (s, 1H), 7.92 (d, J=8.3Hz, 1H), 7.78 (dd, J=5.3, 1.3 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.23 (d,J=7.6 Hz, 1H), 4.11 (s, 3H), 3.91-3.86 (m, 4H), 3.36-3.30 (m, 4H).MS=482 (MH)+.

Example 447(6-Fluoro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(6-Fluoro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and6-Fluoro-pyridin-2-ylamine (30.0 mg, 0.268 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as the free base asan off-white solid (0.003 g, 2%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):10.15 (s, 1H), 8.81 (s, 1H), 8.74 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 8.32(s, 1H), 7.88-7.81 (m, 2H), 7.75 (dd, J=8.1, 2.6 Hz, 1H), 6.59 (dd,J=7.7, 2.3 Hz, 1H), 4.07 (s, 3H), 3.71-3.66 (m, 4H), 2.90-2.85 (m, 4H).MS=433 (MH)+.

Example 448[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methoxy-pyridin-2-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methoxy-pyridin-2-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (124.0 mg, 0.2714 mmol) and6-Methoxy-pyridin-2-ylamine (40.0 mg, 0.322 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as the free base asan off-white solid (0.098 g, 80%). MP=189-191° C. ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 9.79 (s, 1H), 9.04 (s, 1H), 8.73 (s, 1H), 8.37 (d,J=5.2 Hz, 1H), 8.31 (s, 1H), 7.79 (dd, J=5.2, 1.4 Hz, 1H), 7.58 (t,J=7.9 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 6.30 (d, J=7.7 Hz, 1H), 4.07 (s,3H), 4.04 (s, 3H), 3.67-3.62 (m, 4H), 2.89-2.84 (m, 4H). MS=445 (MH)+.

Example 449[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-2-yl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-2-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and6-Trifluoromethyl-pyridin-2-ylamine (43.0 mg, 0.265 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe free base as off-white solid (0.005 g, 5%). ¹HNMR (400 MHz, d6-DMSO,δ, ppm): 10.34 (s, 1H), 8.80-8.78 (m, 2H), 8.42 (d, J=4.7 Hz, 1H), 8.32(s, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.94 (t, J=8.1 Hz, 1H), 7.89 (dd,J=5.1, 1.3 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 4.07 (s, 3H), 3.68-3.63 (m,4H), 2.90-2.85 (m, 4H). MS=483 (MH)+.

Example 450(2-Fluoro-pyridin-3-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(2-Fluoro-pyridin-3-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (124.0 mg, 0.2714 mmol) and2-Fluoro-pyridin-3-ylamine (40.0 mg, 0.357 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.156 g, 86%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.26 (s, 1H), 8.91 (br s, 3H), 8.86(ddd, J=10.0, 8.0, 1.7 Hz, 1H), 8.42 (s, 1H), 8.36 (dd, J=5.5 Hz, 1H),8.19 (s, 1H), 7.81 (dd, J=5.3, 1.3 Hz, 1H), 7.77 (ddd, J=4.6, 1.5, 1.5Hz, 1H), 7.32 (ddd, J=7.9, 4.8, 0.9 Hz, 1H), 4.11 (s, 3H), 3.93-3.87 (m,4H), 3.36-3.30 (m, 4H). MS=433 (MH)+.

Example 451(2-Fluoro-3-methyl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(2-Fluoro-3-methyl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (111.0 mg, 0.2429 mmol) and2-Fluoro-3-methyl-phenylamine (36.0 mg, 0.288 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetris-trifluoroacetic acid salt as a yellow lyophilate (0.146 g, 76%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.04 (br s, 1H), 8.90 (s, 1H), 8.87(br s, 2H), 8.42 (s, 1H), 8.28 (d, J=5.3 Hz, 1H), 8.06 (s, 1H), 7.98 (t,J=7.8 Hz, 1H), 7.73 (dd, J=5.3, 1.3 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H),6.93 (t, J=7.2 Hz, 1H), 4.10 (s, 3H), 3.91-3.86 (m, 4H), 3.35-3.29 (m,4H), 2.28 (d, J=1.8 Hz, 3H). MS=446 (MH)+.

Example 452(2-Fluoro-3-trifluoromethyl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(2-Fluoro-3-trifluoromethyl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (102.0 mg, 0.2232 mmol) and2-Fluoro-3-trifluoromethyl-phenylamine (48.0 mg, 0.268 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe bis-trifluoroacetic acid salt as a yellow lyophilate (0.050 g, 30%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.32 (s, 1H), 8.91 (s, 1H), 8.85 (brs, 2H), 8.63 (ddd, J=7.8, 7.8, 2.3 Hz, 1H), 8.42 (s, 1H), 8.35 (d, J=5.3Hz, 1H), 8.14 (s, 1H), 7.81 (dd, J=5.3, 1.4 Hz, 1H), 7.39-7.30 (m, 2H),4.11 (s, 3H), 3.92-3.86 (m, 4H), 3.36-3.29 (m, 4H). MS=500 (MH)+.

Example 4532,4-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(2,4-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2,4-Difluoro-phenylamine (27.0 L, 0.265 mmol) in an analogous manner toExample 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.059 g, 39%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.03 (s, 1H), 8.90 (s, 1H), 8.87 (brs, 2H), 8.42 (s, 1H), 8.27 (d, J=5.3 Hz, 1H), 8.10 (ddd, J=9.3, 9.3, 6.3Hz, 1H), 8.00 (s, 1H), 7.72 (dd, J=5.4, 1.3 Hz, 1H), 7.31 (ddd, J=11.5,9.0, 2.9 Hz, 1H), 7.11-7.04 (m, 1H), 4.10 (s, 3H), 3.90-3.85 (m, 4H),3.35-3.29 (m, 4H). MS=450 (MH)+.

Example 454[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3,4-trifluoro-phenyl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3,4-trifluoro-phenyl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2,3,4-Trifluoro-phenylamine (28.0 μL, 0.265 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.104 g, 68%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.21 (s, 1H), 8.95-8.85 (m, 3H), 8.42(s, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 7.99-7.91 (m, 1H), 7.77(dd, J=5.3, 1.3 Hz, 1H), 7.33-7.24 (m, 1H), 4.10 (s, 1H), 3.91-3.86 (m,4H), 3.36-3.29 (m, 4H). MS=468 (MH)+.

Example 455[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4,5-trifluoro-phenyl)-amine

[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4,5-trifluoro-phenyl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2188 mmol) and2,4,5-Trifluoro-phenylamine (39.0 mg, 0.265 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as thebis-trifluoroacetic acid salt as a yellow lyophilate (0.027 g, 17%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.21 (s, 1H), 8.91 (s, 1H), 8.86 (brs, 2H), 8.54 (ddd, J=13.6, 8.5, 8.5 Hz, 1H), 8.42 (s, 1H), 8.36 (d,J=5.4 Hz, 1H), 8.14 (s, 1H), 7.79 (dd, J=5.3, 1.4 Hz, 1H), 7.60 (ddd,J=10.9, 10.9, 7.7 Hz, 1H), 4.10 (s, 3H), 3.91-3.86 (m, 4H), 3.36-3.29(m, 4H). MS=468 (MH)+.

Example 456(3S,4S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolor(3R,4R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol

(3S,4S)- or(3R,4R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolwas prepared from(1)-trans-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol(67.52 mg) via super critical fluid chiral chromatography usingChiralcel OJ-H (10×250 mm) column using 30% MeOH (w/ 0.1% diethylaminemodifier):70% CO2 eluent at 6.0 mL/min over 4 injections of 150 L, T=35°C., P=120 bar, UV=220 nm. Product isolated as the initial peak as ayellow solid (0.0166 g, 24%). Purity: >99% ee @100% purity. RT: 8.6 min,¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.31 (s, 1H), 8.80 (s, 1H), 8.33 (s,1H), 8.31 (d, J=5.4 Hz, 1H), 7.90 (s, 1H), 7.77-7.74 (m, 2H), 7.67 (dd,J=5.3, 1.3 Hz, 1H), 7.30-7.25 (m, 2H), 6.92-6.87 (m, 1H), 5.01-4.98 (m,1H), 4.94 (d, J=4.1 Hz, 1H), 4.11-3.94 (m, 5H), 3.55-3.38 (m, 3H),3.16-3.10 (m, 1H), 2.08-2.00 (m, 1H), 1.57-1.47 (m, 1H). MS=445 (MH)+.

Example 457(3R,4R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolor(3S,4S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol

(3R,4R)- or(3S,4S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolwas prepared from(±)-trans-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol(67.52 mg) via super critical fluid chiral chromatography usingChiralcel OJ-H (10×250 mm) column using 30% MeOH (w/ 0.1% diethylaminemodifier):70% CO2 eluent at 6.0 mL/min over 4 injections of 150 L, T=35°C., P=120 bar, UV=220 nm. Product isolated as the secondary peak as ayellow solid (0.0209 g, 31%). Purity: >97.6% ee @98% purity. RT: 12.98min. ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.32 (s, 1H), 8.80 (s, 1H), 8.33(s, 1H), 8.31 (d, J=5.2 Hz, 1H), 7.90 (s, 1H), 7.77-7.74 (m, 2H), 7.67(dd, J=5.4, 1.3 Hz, 1H), 7.30-7.25 (m, 2H), 6.92-6.87 (m, 1H), 5.02-4.98(m, 2H), 4.11-3.93 (m, 5H), 3.55-3.37 (m, 3H), 3.16-3.10 (m, 1H),2.08-2.00 (m, 1H), 1.57-1.47 (m, 1H). MS=445 (MH)+.

Example 4583-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-propionamide

458a)3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-propionamidewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1.00 g,3.46 mmol) and 3-Amino-propionamide; hydrochloride (0.52 g, 4.2 mmol) inan analogous manner to [B016]. Product isolated as a tan solid (0.303 g,24%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.93 (t, J=5.5 Hz, 1H), 8.79 (s,1H), 8.61-8.58 (m, 1H), 8.35 (s, 1H), 8.34-8.32 (m, 2H), 7.50 (br s,1H), 7.00 (br s, 1H), 4.11 (s, 3H), 3.94-3.87 (m, 2H), 2.57-2.52 (m,2H). MS=359, 361 (MH)+. 458b)3-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-propionamidewas prepared from3-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ylamino]-propionamide(100.0 mg, 0.2787 mmol) and Aniline (30.0 L, 0.329 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as thetrifluoroacetic acid salt as a yellow lyophilate (0.043 g, 28%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 9.55 (br s, 1H), 8.88 (t, J=5.4 Hz, 1H),8.77 (s, 1H), 8.34 (s, 1H), 8.26 (d, J=5.4 Hz, 1H), 7.96 (s, 1H),7.74-7.69 (m, 3H), 7.50 (s, 1H), 7.33 (t, J=7.9 Hz, 2H), 7.04-6.95 (m,2H), 4.12 (s, 3H), 3.95-3.89 (m, 2H), 2.58-2.53 (m, 2H). MS=416 (MH)+.

Example 459[4-(5-Methoxy-4-piperidin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine

459a)2-(2-Chloro-pyridin-4-yl)-5-methoxy-4-piperidin-1-yl-pyrido[3,4-d]pyrimidinewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1.0 g,3.5 mmol) and Piperidine (0.41 mL, 4.2 mmol) in an analogous manner to[B016]. Product isolated as a yellow-orange solid (0.61 g, 49%). ¹HNMR(400 MHz, d6-DMSO, δ, ppm): 8.83 (s, 1H), 8.59 (d, J=5.0 Hz, 1H), 8.35(s, 1H), 8.31-8.28 (m, 2H), 4.08 (s, 3H), 3.71-3.65 (m, 4H), 1.75-1.65(m, 6H).

MS=356, 358 (MH)+.

459b)[4-(5-Methoxy-4-piperidin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-aminewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-4-piperidin-1-yl-pyrido[3,4-d]pyrimidine(100.0 mg, 0.2810 mmol) and Aniline (31.0 L, 0.340 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as the freebase as a yellow solid (0.075 g, 64%). MP=221-223° C. ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 9.31 (s, 1H), 8.80 (s, 1H), 8.32 (s, 1H), 8.30 (d,J=5.2 Hz, 1H), 7.90 (s, 1H), 7.77-7.73 (m, 2H), 7.66 (dd, J=5.2, 1.3 Hz,1H), 7.30-7.25 (m, 2H), 6.92-6.87 (m, 1H), 4.08 (s, 3H), 3.70-3.65 (m,4H), 1.75-1.67 (m, 6H). MS=413 (MH)+.

Example 460{4-[4-(4,4-Difluoro-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine

460a)2-(2-Chloro-pyridin-4-yl)-4-(4,4-difluoro-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidinewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1.0 g,3.5 mmol) and 4,4-Difluoro-piperidine; hydrochloride (0.66 g, 4.2 mmol)in an analogous manner to [B016]. Product isolated as an orange solid(0.806 g, 59%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.90 (s, 1H), 8.61(dd, J=4.9, 0.8 Hz, 1H), 8.41 (s, 1H), 8.34-8.31 (m, 2H), 4.10 (s, 3H),3.84-3.79 (m, 4H), 2.26-2.14 (m, 4H). MS=392, 394 (MH)+. 460b){4-[4-(4,4-Difluoro-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-aminewas prepared from2-(2-Chloro-pyridin-4-yl)-4-(4,4-difluoro-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidine(100.0 mg, 0.2552 mmol) and Aniline (28.0 L, 0.307 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as the freebase as an orange solid (0.027 g, 23%). ¹HNMR (400 MHz, d6-DMSO, δ,ppm): 9.32 (s, 1H), 8.87 (s, 1H), 8.38 (s, 1H), 8.32 (d, J=5.2 Hz, 1H),7.92 (s, 1H), 7.78-7.74 (m, 2H), 7.68 (dd, J=5.3, 1.4 Hz, 1H), 7.31-7.25(m, 2H), 6.93-6.88 (m, 1H), 4.10 (s, 3H), 3.82-3.78 (m, 4H), 2.27-2.15(m, 4H). MS=449 (MH)+.

Example 4611-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-4-carbonitrile

461a)1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-4-carbonitrilewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1.0 g,3.5 mmol) and Piperidine-4-carbonitrile (0.46 g, 4.2 mmol) in ananalogous manner to [B016]. Product isolated as an orange solid (0.80 g,61%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.87 (s, 1H), 8.61 (dd, J=5.0,0.7 Hz, 1H), 8.39 (s, 1H), 8.34-8.31 (m, 2H), 4.10 (s, 3H), 3.96-3.88(m, 2H), 3.57-3.49 (m, 2H), 3.25-3.17 (m, 1H), 2.14-2.05 (m, 2H),1.96-1.86 (m, 2H). MS=381, 383 (MH)+.

461b)1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-4-carbonitrilewas prepared from1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-4-carbonitrile(100.0 mg, 0.2626 mmol) and Aniline (29.0 L, 0.318 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as the freebase as a yellow solid (0.090 g, 77%). MP=242-244° C. ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 9.32 (s, 1H), 8.84 (s, 1H), 8.36 (s, 1H), 8.31 (d,J=5.2 Hz, 1H), 7.91 (s, 1H), 7.77-7.74 (m, 2H), 7.67 (dd, J=5.4, 1.4 Hz,1H), 7.31-7.26 (m, 2H), 6.93-6.88 (m, 1H), 4.09 (s, 3H), 3.96-3.88 (m,2H), 3.56-3.48 (m, 2H), 3.26-3.19 (m, 1H), 2.15-2.06 (m, 2H), 1.98-1.88(m, 2H). MS=438 (MH)+.

Example 462{4-[4-(4-Fluoro-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine

462a)2-(2-Chloro-pyridin-4-yl)-4-(4-fluoro-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidinewas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (1.0 g,3.5 mmol) and 4-Fluoro-piperidine; hydrochloride (0.58 g, 4.2 mmol) inan analogous manner to [B016]. Product isolated as an orange solid (0.61g, 47%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.87 (s, 1H), 8.61 (dd,J=4.9, 0.7 Hz, 1H), 8.38 (s, 1H), 8.33-8.30 (m, 2H), 5.08-4.90 (m, 1H),4.09 (s, 3H), 3.83-3.68 (m, 4H), 2.16-2.00 (m, 2H), 1.97-1.85 (m, 2H).MS=374, 376 (MH)+. 462b){4-[4-(4-Fluoro-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-aminewas prepared from2-(2-Chloro-pyridin-4-yl)-4-(4-fluoro-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidine(100.0 mg, 0.2675 mmol) and Aniline (30.0 L, 0.329 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as the freebase as a yellow solid (0.057 g, 49%). MP=202-205° C. ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 9.32 (s, 1H), 8.83 (s, 1H), 8.35 (s, 1H), 8.31 (d,J=5.3 Hz, 1H), 7.91 (s, 1H), 7.77-7.74 (m, 2H), 7.67 (dd, J=5.3, 1.3 Hz,1H), 7.31-7.25 (m, 2H), 6.92-6.87 (m, 1H), 5.10-4.90 (m, 1H), 4.09 (s,3H), 3.84-3.67 (m, 4H), 2.17-2.02 (m, 2H), 1.98-1.85 (m, 2H). MS=431(MH)+.

Example 463(3R,4S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolor(3S,4R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol

(3R,4S)- or(3S,4R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolwas prepared from(±)-cis-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolvia super critical fluid chiral chromatography was performed using aChiralpak AD-H (10×250 mm) column using 40% MeoH (w/ 0.1% diethylaminemodifier):60% CO2 eluent at 6.0 mL/min over 2 injections of 400 L, T=35°C., P=120 bar, UV=220 nm. Product isolated as the initial peak as ayellow solid (0.0254 g, 38%). Purity: >99% ee @100% purity. RT: 9.4 min.¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.32 (s, 1H), 8.79 (s, 1H), 8.32-8.29(m, 2H), 7.90 (s, 1H), 7.77-7.73 (m, 2H), 7.67 (dd, J=5.3, 1.4 Hz, 1H),7.30-7.25 (m, 2H), 6.92-6.87 (m, 1H), 4.63 (br s, 2H), 4.07 (s, 3H),4.00-3.88 (m, 1H), 3.84-3.72 (m, 2H), 3.65-3.52 (m, 3H), 1.97-1.88 (m,1H), 1.75-1.68 (m, 1H). MS=445 (MH)+.

Example 464(3S,4R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolor(3R,4S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol

(3S,4R)- or(3R,4S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolwas prepared from(±)-cis-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diolvia super critical fluid chiral chromatography was performed using aChiralpak AD-H (10×250 mm) column using 40% MeOH (w/ 0.1% diethylaminemodifier):60% CO2 eluent at 6.0 mL/min over 2 injections of 400 L, T=35°C., P=120 bar, UV=220 nm. Product isolated as the secondary peak as ayellow solid (0.0255 g, 38%). Purity: >99% ee @100% Purity. RT: 8.6 min.¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.32 (s, 1H), 8.79 (s, 1H), 8.32-8.29(m, 2H), 7.90 (s, 1H), 7.77-7.74 (m, 2H), 7.67 (dd, J=5.2, 1.3 Hz, 1H),7.30-7.25 (m, 2H), 6.92-6.87 (m, 1H), 4.64 (br s, 2H), 4.07 (s, 3H),3.99-3.73 (m, 3H), 3.65-3.54 (m, 3H), 1.97-1.87 (m, 1H), 1.76-1.66 (m,1H). MS=445 (MH)+.

Example 465{(R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanol

465a){(R)-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanolwas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (0.50 g,1.7 mmol) and (R)-3-Hydroxymethyl-pyrrolidine-1-carboxylic acidtert-butyl ester (0.42 g, 2.1 mmol) [deprotected with 1:1trifluoroacetic acid:methylene chloride before addition] in an analogousmanner to [B016]. Product isolated as a yellow foam (0.186 g, 28%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.78 (s, 1H), 8.59 (dd, J=5.0, 0.6 Hz,1H), 8.34 (s, 1H), 8.32-8.29 (m, 2H), 4.72 (br s, 1H), 4.07 (s, 3H),3.90-3.37 (m, 6H), 2.37 (br s, 1H), 1.99 (br s, 1H), 1.68 (br s, 1H).MS=372, 374 (MH)+.

465b){(R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanolwas prepared from{(R)-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanol(186.0 mg, 0.5002 mmol) and Aniline (55.0 L, 0.604 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as the freebase as a yellow solid (0.091 g, 42%). MP=208-209° C. ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 9.31 (s, 1H), 8.75 (s, 1H), 8.30 (s, 1H), 8.29 (d,J=5.2 Hz, 1H), 7.90 (s, 1H), 7.78-7.74 (m, 2H), 7.68 (dd, J=5.3, 1.3 Hz,1H), 7.30-7.25 (m, 2H), 6.91-6.86 (m, 1H), 4.73 (br s, 1H), 4.07 (s,3H), 3.88-3.35 (m, 6H), 2.37 (br s, 1H), 2.00 (br s, 1H), 1.70 (br s,1H). MS=429 (MH)+.

Example 466{(S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanol

466a) desired{(S)-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanolwas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (0.50 g,1.7 mmol) and (S)-3-Hydroxymethyl-pyrrolidine-1-carboxylic acidtert-butyl ester (0.42 g, 2.1 mmol) [deprotected with 1:1trifluoroacetic acid:methylene chloride before addition] in an analogousmanner to [B016]. Product isolated as a yellow resin (0.185 g, 29%).¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.78 (s, 1H), 8.59 (d, J=5.0 Hz, 1H),8.34 (s, 1H), 8.32-8.29 (m, 2H), 4.72 (br s, 1H), 4.07 (s, 3H),3.90-3.35 (m, 6H), 2.42 (br s, 1H), 1.99 (br s, 1H), 1.70 (br s, 1H).MS=372, 374 (MH)+. 466b){(S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanolwas prepared from{(S)-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanol(185.0 mg, 0.4976 mmol) and Aniline (55.0 L, 0.604 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as the freebase as a yellow foam (0.093 g, 43%). MP=210-211° C. ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 9.31 (s, 1H), 8.75 (s, 1H), 8.30 (s, 1H), 8.29 (d,J=5.3 Hz, 1H), 7.90 (s, 1H), 7.78-7.74 (m, 2H), 7.68 (dd, J=5.3, 1.4 Hz,1H), 7.30-7.25 (m, 2H), 6.92-6.86 (m, 1H), 4.73 (br s, 1H), 4.07 (s,1H), 3.88-3.35 (m, 6H), 2.37 (br s, 1H), 2.00 (br s, 1H), 1.71 (br s,1H). MS=429 (MH)+.

Example 467(meso)-cis-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-azepane-4,5-diol

467a) To a round bottom flask equipped a stir bar and a reflux condensercontaining But-3-enylamine (0.58 g, 8.1 mmol) and Tetrahydrofuran (50mL) was added 4-Bromo-but-1-ene (1.0 g, 7.4 mmol) and the mixture washeated at 60° C. for 18 hours. The mixture was cooled to roomtemperature. Triethylamine (1.1 mL, 8.1 mmol) was added followedDi-tert-Butyldicarbonate (1.8 g, 8.1 mmol). The suspension was stirredat room temperature for 1 hour. The suspension was filtered through aplug of diatomaceous earth and the filtrate was evaporated to a yellowsuspension. To the residue was added methanol (40 mL) followed by INaqueous Sodium hydroxide (5 mL). The mixture was stirred for 1 hour. Theresulting suspension was filtered through a plug of diatomaceous earth.The filtrate was evaporated. The residue was purified via chromatographyusing an ISCO apparatus (silica gel column 24 g 0%-5% EthylAcetate:Hexane). Di-but-3-enyl-carbamic acid tert-butyl ester wasisolated as clear oil (0.304 g, 18%). ¹HNMR (400 MHz, CDCl3, δ, ppm):5.83-5.70 (m, 2H), 5.10-4.99 (m, 4H), 3.23 (br s, 4H), 2.31-2.24 (m,4H), 1.46 (s, 9H). MS=248 (M+Na)+.

467b) To a solution of Di-but-3-enyl-carbamic acid tert-butyl ester(0.30 g, 1.3 mmol) in dry Toluene (30 mL) under an atmosphere ofNitrogen was added(1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium(45.0 mg, 0.0717 mmol). The mixture was heated at 50° C. for 5 hours.The mixture was cooled to room temperature and stirred overnight. Thevolatiles were evaporated. The residue was triturated with hexane (30mL) and the suspension was filtered through a plug of diatomaceousearth. The filtrate was evaporated. The residue was purified viachromatography using an ISCO apparatus (silica gel column 24 g with0%→5% Ethyl Acetate:Hexane). 2,3,6,7-Tetrahydro-azepine-1-carboxylicacid tert-butyl ester was isolated as a clear oil (0.166 g, 63%). ¹HNMR(400 MHz, CDCl3, δ, ppm): 5.79-5.66 (m, 2H), 3.50-3.38 (m, 4H), 2.28 (brs, 4H), 1.47 (s, 9H). MS=220 (M+Na)+. 467c)(meso)-cis-4,5-Dihydroxy-azepane-1-carboxylic acid tert-butyl ester wasprepared from 2,3,6,7-Tetrahydro-azepine-1-carboxylic acid tert-butylester (0.166 g, 0.841 mmol) in an analogous manner to Example 436a.Product isolated as an off-white solid (0.151 g, 77%). ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 4.48 (d, J=4.3 Hz, 2H), 3.67-3.60 (m, 2H), 3.45-3.32(m, 2H), 3.19-3.05 (m, 2H), 1.84-1.73 (m, 2H), 1.64-1.52 (m, 2H), 1.38(s, 9H). MS=254 (M+Na)+. 467d)(meso)-cis-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-azepane-4,5-diolwas prepared from2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (0.20 g,0.69 mmol), and (meso)-cis-4,5-Dihydroxy-azepane-1-carboxylic acidtert-butyl ester (0.15 g, 0.65 mmol) [deprotected with 1:1trifluoroacetic acid:methylene chloride before addition] in an analogousmanner to [B016]. Product isolated as an orange resin (0.115 g, 44%).¹HNMR (400 MHz,d6-DMSO, δ, ppm): 8.77 (s, 1H), 8.59 (dd, J=4.8, 1.0 Hz,1H), 8.32-8.28 (m, 3H), 4.45-4.42 (m, 2H), 4.04 (s, 3H), 3.88-3.60 (m,6H), 2.10-2.00 (m, 2H), 1.86-1.77 (m, 2H). MS=402, 404 (MH)+.

467e)(meso)-cis-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-azepane-4,5-diolwas prepared from(meso)-cis-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-azepane-4,5-diol(115.0 mg, 0.2862 mmol) and Aniline (33.0 L, 0.362 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as the freebase as a yellow foam (0.033 g, 25%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):9.29 (s, 1H), 8.74 (s, 1H), 8.29 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 7.90(s, 1H), 7.77-7.74 (m, 2H), 7.67 (dd, J=5.3, 1.3 Hz, 1H), 7.30-7.25 (m,2H), 6.92-6.87 (m, 1H), 4.45 (d, J=4.2 Hz, 2H), 4.05 (s, 3H), 3.87-3.60(m, 6H), 2.12-2.02 (m, 2H), 1.87-1.78 (m, 2H). MS=459 (MH)+.

Example 4681-{2-[2-(6-Fluoro-pyridin-2-ylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ol

1-{2-[2-(6-Fluoro-pyridin-2-ylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-olwas prepared from1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol(90.0 mg, 0.242 mmol) and 6-Fluoro-pyridin-2-ylamine (33.0 mg, 0.294mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the free base as a yellow foam (0.048 g, 35%). ¹HNMR (400MHz, d6-DMSO, δ, ppm): 10.43 (br s, 1H), 8.83 (s, 1H), 8.71 (s, 1H),8.43 (d, J=5.3 Hz, 1H), 8.36 (s, 1H), 7.92-7.85 (m, 2H), 7.69-7.65 (m,1H), 6.65 (dd, J=7.9, 2.2 Hz, 1H), 4.11-4.01 (m, 5H), 3.87-3.80 (m, 1H),3.51-3.42 (m, 2H), 1.97-1.89 (m, 2H), 1.64-1.54 (m, 2H). MS=448 (MH)+.

Example 4691-{5-Methoxy-2-[2-(6-methoxy-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ol

1-{5-Methoxy-2-[2-(6-methoxy-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-olwas prepared from1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol(90.0 mg, 0.242 mmol) and 6-Methoxy-pyridin-2-ylamine (36.0 mg, 0.290mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the free base as a yellow foam (0.031 g, 27%). ¹HNMR (400MHz, d6-DMSO, δ, ppm): 10.45 (br s, 1H), 8.86 (s, 1H), 8.78 (s, 1H),8.43 (d, J=5.6 Hz, 1H), 8.36 (s, 1H), 7.90 (d, J=6.0 Hz, 1H), 7.69 (t,J=7.9 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.44 (d, J=8.0 Hz, 1H), 4.10-3.98(m, 8H), 3.87-3.80 (m, 1H), 3.48-3.39 (m, 2H), 1.97-1.89 (m, 2H),1.63-1.53 (m, 2H). MS=460 (MH)+.

Example 470((S)-1-{2-[2-(6-Fluoro-pyridin-2-ylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-pyrrolidin-3-yl)-methanol

((S)-1-{2-[2-(6-Fluoro-pyridin-2-ylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-pyrrolidin-3-yl)-methanolwas prepared from{(S)-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanol(90.0 mg, 0.242 mmol) and 6-Fluoro-pyridin-2-ylamine (40.0 mg, 0.357mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.026g, 19%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.43 (br s, 1H), 8.79 (s,1H), 8.68 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.37 (s, 1H), 7.92-7.85 (m,2H), 7.68 (d, J=7.9 Hz, 1H), 6.65 (d, J=8.0 Hz, 1H), 4.09 (s, 3H),3.92-3.40 (m, 6H), 2.45-2.30 (m, 1H), 2.08-1.98 (m, 1H), 1.80-1.65 (m,1H). MS=448 (MH)+.

Example 471((S)-1-{5-Methoxy-2-[2-(6-methoxy-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-pyrrolidin-3-yl)-methanol

((S)-1-{5-Methoxy-2-[2-(6-methoxy-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-pyrrolidin-3-yl)-methanolwas prepared from{(S)-1-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanol(90.0 mg, 0.242 mmol) and 6-Methoxy-pyridin-2-ylamine (45.0 mg, 0.362mmol) in an analogous manner to Example 303c and Example 1501c. Productisolated as the trifluoroacetic acid salt as a yellow lyophilate (0.044g, 31%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 10.44 (br s, 1H), 8.86 (s,1H), 8.73 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=5.0Hz, 1H), 7.68 (t, J=8.2 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.44 (d, J=7.8Hz, 1H), 4.08 (s, 3H), 4.04 (s, 3H), 3.90-3.35 (m, 6H), 2.45-2.30 (m,1H), 2.05-1.95 (m, 1H), 1.77-1.64 (m, 1H). MS=460 (MH)+.

Example 4732-(4-Cyano-phenyl)-N-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide

2-(4-Cyano-phenyl)-N-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamidewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2141 mmol) and2-(4-Cyano-phenyl)-acetamide (50.0 mg, 0.312 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as the freebase as a tan solid (0.094 g, 89%). MP=200-203° C.

¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.05 (s, 1H), 8.97 (s, 1H), 8.49 (dd,J=5.1, 0.6 Hz, 1H), 8.09 (s, 1H), 8.04 (dd, J=5.2, 1.4 Hz, 1H),7.84-7.81 (m, 2H), 7.60-7.57 (m, 2H), 3.91 (s, 2H), 3.85-3.45 (m, 4H),2.83 (m, 4H), 2.63-2.55 (m, 1H), 1.28-1.22 (m, 2H), 1.04-0.99 (m, 2H).LC/MS=491 (MH)+.

Example 474[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-methyl-4-morpholin-4-yl-phenyl)-amine

[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyridin-2-yl)-pyridin-2-yl]-(2-methyl-4-morpholin-4-yl-phenyl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2141 mmol) and2-Methyl-4-morpholin-4-yl-phenylamine (61.0 mg, 0.317 mmol) in ananalogous manner to Example 303c and Example 1501c. Product isolated asthe free base as an orange-brown solid (0.085 g, 75%). MP=214-220° C.¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.93 (s, 1H), 8.23 (s, 1H), 8.14 (d,J=5.3 Hz, 1H), 8.07 (s, 1H), 7.58 (s, 1H), 7.52 (dd, J=5.2, 1.3 Hz, 1H),7.28 (d, J=8.6 Hz, 1H), 6.86 (d, J=2.7 Hz, 1H), 6.79 (dd, J=8.6, 2.8 Hz,1H), 3.80-3.50 (m, 8H), 3.10-3.06 (m, 4H), 2.81 (br s, 4H), 2.64-2.56(m, 1H), 2.19 (s, 3H), 1.27-1.21 (m, 2H), 1.04-0.99 (m, 2H).

LC/MS=523 (MH)+.

Example 475[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-morpholin-4-yl-pyridin-3-yl)-amine

[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-morpholin-4-yl-pyridin-3-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (107.0 mg, 0.2291 mmol) and6-Morpholin-4-yl-pyridin-3-ylamine (57.0 mg, 0.318 mmol) in an analogousmanner to Example 303c and Example 1501c. Product isolated as the freebase as a yellow solid (0.103 g, 87%). MP=217-219C. ¹HNMR (400 MHz,d6-DMSO, δ, ppm): 9.08 (s, 1H), 8.96 (s, 1H), 8.45 (d, J=2.6 Hz, 1H),8.24 (d, J=5.4 Hz, 1H), 8.09 (s, 1H), 7.99 (dd, J=9.1, 2.7 Hz, 1H), 7.81(s, 1H), 7.62 (dd, J=5.3, 1.3 Hz, 1H), 6.85 (d, J=9.1 Hz, 1H), 3.90-3.50(m, 8H), 3.37-3.34 (m, 4H), 2.86 (br s, 4H), 2.66-2.58 (m, 1H),1.29-1.23 (m, 2H), 1.05-1.00 (m, 2H). LC/MS=510 (MH)+.

Example 476[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyridin-3-yl-amine

[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyridin-3-yl-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2141 mmol) and 3-aminopyridine (30.0mg, 0.319 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the free base as a pale yellow solid (0.067g, 74%). MP=226-228° C. ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 9.55 (s, 1H),8.98 (s, 1H), 8.87 (d, J=2.5 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H), 8.32-8.28(m, 1H), 8.12-8.09 (m, 2H), 7.95 (s, 1H), 7.75 (dd, J=5.3, 1.2 Hz, 1H),7.30 (dd, J=8.4, 4.7 Hz, 1H), 3.96-3.46 (m, 4H), 2.87 (br s, 4H),2.66-2.58 (m, 1H), 1.30-1.23 (m, 2H), 1.06-1.01 (m, 2H). LC/MS=425.0(MH)+.

Example 477(2-Chloro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

(2-Chloro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2141 mmol) and o-Chloroaniline (52.0uL, 0.315 mmol) in an analogous manner to Example 303c and Example1501c. Product isolated as the free base as an orange foam (0.086 g,88%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm): 8.97 (s, 1H), 8.68 (s, 1H), 8.26(d, J=5.3 Hz, 1H), 8.09 (s, 1H), 8.04-8.00 (m, 2H), 7.72 (dd, J=5.3, 1.4Hz, 1H), 7.48 (dd, J=8.0, 1.5 Hz, 1H), 7.34-7.29 (m, 1H), 7.09-7.04 (m,1H), 3.96-3.46 (m, 4H), 2.86 (br s, 4H), 2.65-2.57 (m, 1H), 1.29-1.23(m, 2H), 1.05-1.00 (m, 2H). LC/MS=458.0 (MH)+.

Example 478[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methyl-pyridin-3-yl)-amine

[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methyl-pyridin-3-yl)-aminewas prepared from4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100.0 mg, 0.2141 mmol) and4-Methyl-pyridin-3-ylamine (34.0 mg, 0.314 mmol) in an analogous mannerto Example 303c and Example 1501c. Product isolated as the free base asa pale yellow foam (0.070 g, 74%). ¹HNMR (400 MHz, d6-DMSO, δ, ppm):8.98 (s, 1H), 8.81 (s, 1H), 8.64 (s, 1H), 8.22 (d, J=5.4 Hz, 1H), 8.16(d, J=4.9 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.67 (dd, J=5.2, 1.3 Hz,1H), 7.25 (d, J=4.9 Hz, 1H), 3.95-3.45 (m, 4H), 2.93 (br s, 4H),2.65-2.59 (m, 1H), 2.28 (s, 3H), 1.29-1.23 (m, 2H), 1.06-1.01 (m, 2H).LC/MS=439.2 (MH)+.

Example 481[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine

481a) 3-Bromo-5-fluoro-isonicotinic acid tert-butyl ester (1.9 g, 6.9mmol), cyclopropyltrifluoroborate (1.18 g, 7.97 mmol), palladium acetate(81.3 mg, 0.36 mmol), butyl-ditricyclo[3.3.1.1(3,7)]decan-1-yl-phosphane(194.8 mg, 0.54 mmol), and cesium carbonate (7 g, 21.7 mmol) was heatedat 85° C. in toluene (35 mL)/water (4 mL) overnight, under nitrogen.Cooled, partitioned between ether and water. Organic extracts dried(MgSO₄), filtered, solvent evaporated; product isolated by flashchromatography (ISCO, Silica gel, EtOAc/Hexanes 0-10%; 2nd fraction isproduct): 3-cyclopropyl-5-fluoro-isonicotinic acid tert-butyl ester (50%yield). 481b) 3-Cyclopropyl-5-fluoro-isonicotinic acid tert-butyl ester(700.0 mg, 2.95 mmol) was treated with trifluoroacetic acid (2.0 mL,26.0 mmol) in methylene chloride (5 mL) at 25° C. overnight. Solvent wasevaporated, and the crude residue was dried on high vacuum, and thenused without further purification: 3-cyclopropyl-5-fluoro-isonicotinicacid; compound with trifluoro-acetic acid (quant.).

481c) 3-Cyclopropyl-5-fluoro-isonicotinic acid; compound withtrifluoro-acetic acid (995 mg, 3.37 mmol) and2-chloro-isonicotinamidine; hydrochloride (1.3 g, 6.7 mmol) were treatedwith N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (1.35 g, 3.54 mmol) and N,N-diisopropylethylamine(3.5 mL, 20.2 mmol) in N,N-dimethylformamide (14 mL) at room temperatureovernight. The reaction mixture was partitioned between DCM and water,organic layer washed extensively with water, dried (MgSO₄), solventevaporated when a precipitate formed. Trituration from ether followed byfiltration affordedN-[(2-chloro-pyridin-4-yl)-imino-methyl]-3-cyclopropyl-5-fluoro-isonicotinamide,which was used in the next step without further purification.

481d)N-[(2-Chloro-pyridin-4-yl)-imino-methyl]-3-cyclopropyl-5-fluoro-isonicotinamide(solid product from step c) and cesium carbonate (1.4 g, 4.2 mmol) weremixed in N,N-dimethylacetamide (17 mL). The reaction was microwaved on300 watts, 120° C. for 20 minutes. Reaction mixture was diluted withice/water and neutralized with AcOH to pH 5 at 0 OC, and the precipitatewas collected by filtation, washed with water and dried:2-(2-chloro-pyridin-4-yl)-5-cyclopropyl-3H-pyrido[3,4-d]pyrimidin-4-one(33% yield over 2 steps). 481e) A suspension of2-(2-chloro-pyridin-4-yl)-5-cyclopropyl-3H-pyrido[3,4-d]pyrimidin-4-one(0.85 g, 2.8 mmol), triethylamine (1.3 mL, 9.3 mmol) and4-dimethylaminopyridine (43.0 mg, 0.352 mmol) in N,N-dimethylformamide(10 mL, 100 mmol) was treated with 2,4,6-triisopropylbenzenesulfonylchloride (0.98 g, 3.2 mmol) and the mixture was stirred at roomtemperature for 1 hour. tert-Butyl-1-piperazinecarboxylate (0.65 g, 3.5mmol) was added and the mixture was stirred at room temperatureovernight. Water (40 mL) was added and the mixture was stirredvigorously for 1 hour. The suspension was filtered, rinsed with waterand dried. The solid was dissolved in DCM, the solution was dried(MgSO₄), filtered and the solvent was evaporated under vacuum. Theproduct was isolated by flash chromatography (Isco, Silica Gel, 20%→100%Ethyl Acetate/Hexane):4-[2-(2-chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester, tan solid (1.03 g).

481f) A reaction tube was charged with4-[2-(2-chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (200 mg, 0.428 mmol), aniline (43.9 L, 0.482mmol), palladium acetate (16 mg, 0.07 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (38.8 mg, 0.067 mmol),and cesium carbonate (366 mg, 1.125 mmol) in 1,4-dioxane (2 mL). Thetube was evacuated and back-filled with nitrogen three times, and thenflushed with argon, capped, and heated at 100° C. for 3 h. The reactionmixture was cooled to room temperature and partitioned between ether andwater. The organic extracts were dried (MgSO₄), then the solvent wasevaporated under reduced pressure. The product was used in the next stepwithout further purification. The crude product obtained in step 1 wastreated with trifluoroacetic acid (1.48 mL, 19.2 mmol) in methylenechloride (5.92 mL) at room temperature until reaction was complete (byhplc); approx. 1h. The volatiles were evaporated under reduced pressureand the product was isolated by reverse phase chromatography (Gilson)followed by neutralization by cation-exchange column (Strata, fromPhenomenex) filtration and releasing with methanolic ammonia:[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine(133 mg, 73% yield over 2 steps); bright yellow solid; MP: 221-226 C;¹H-NMR (CDCl₃) δ: 9.11 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.04 (s, 1H),8.00 (s, 1H), 7.80 (dd, J=5.2; 1.3 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.37(dd, J=8.4; 8.4 Hz, 2H), 7.07 (t, J=8.4 Hz, 1H), 6.68 (br s, 1H), 3.75(br s, 4H), 3.01 (m, 4H), 269 (m, 1H), 1.59 (water and exhcangeable NH),1.26 (m, 2H), 1.00 (m, 2H); LC/MS (ESI+): 424.17 (M+H).

Example 4822-{4-[5-Cyclopropyl-4-(4-hydroxy-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile

This product was prepared from2-(2-chloro-pyridin-4-yl)-5-cyclopropyl-3H-pyrido[3,4-d]pyrimidin-4-oneaccording to a procedure similar to Example 481e,f: white solid; ¹H NMR(dmso-d) δ: 10.40 (s, 1H), 8.98 (s, 1H), 8.64 (br s, 1H), 8.49 (dd,J=6.0; 0.4 Hz, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.37 (br s, 1H), 8.10 (s,1H), 7.88 (dd, J=5.2; 1.4 Hz, 1H), 7.30 (dd, J=6.0; 1.4 Hz, 1H), 7.81(br s, 1H), 4.11 (m, 2H), 3.80 (br s, 1H), 3.50 (br s, 2H), 2.60 (br s,1H), 1.90 (m, 2H), 1.52 (br s, 1H), 1.26 (m, 2H), 1.04 (m, 2H); LC/MS(ESI+): 465.2 (M+H).

Example 483[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-fluoro-pyridin-2-yl)-amine

This product was prepared from2-(2-chloro-pyridin-4-yl)-5-cyclopropyl-3H-pyrido[3,4-d]pyrimidin-4-oneaccording to a procedure similar to Example 481e,f: yellow lyophilate;¹H NMR (dmso-d₆) δ: 10.40 (s, 1H), 9.08 (s, 1H), 9.03 (br s, 2H), 8.81(s, 1H), 8.45 (d, J=5.3 Hz, 1H), 8.20 (s, 1H), 7.92 (m, 1H), 7.86 (m,1H), 7.69 (m, 1H), 6.65 (m, 1H), 3.97 (br s, 4H), 3.34 (br s, 4H), 2.69(m, 1H), 1.27 (m, 2H), 1.09 (m, 2H); LC/MS (ESI+): 443.2 (M+H).

Example 484[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-phenyl)-amine

This product was prepared from4-[2-(2-chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester according to a procedure similar to Example 481f:off-white foam; ¹H-NMR (CDCl₃) δ: 9.12 (s, 1H), 8.39 (d, J=5.3 Hz, 1H),8.23 (m, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.85 (m, 1H), 7.14 (m, 2H),6.97 (m, 2H), 6.86 (br s, 1H), 3.76 (br s, 4H), 3.03 (m, 4H), 2.69 (m,1H), 1.93 (br s, water and exch. protons), 1.27 (m, 2H), 1.01 (m, 2H);LC/MS (ESI+): 442.1 (M+H).

Example 485(±)-2-{4-[5-Cyclopropyl-4-cis-3,4-dihydroxy-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile

This product was prepared from2-(2-chloro-pyridin-4-yl)-5-cyclopropyl-3H-pyrido[3,4-d]pyrimidin-4-oneaccording to a procedure similar to Example 481e,f: tan solid; ¹H-NMR(CDCl₃) δ: 9.18 (s, 1H), 8.52 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.39 (m,2H), 8.15 (m, 2H), 7.93 (m, 1H), 7.04 (m, 1H), 3.95 (m, 7H), 2.78 (br s,1H), 2.60 (m, 1H), 1.87 (m, 2H), 1.63 (br s, water), 1.27 (m, 2H), 1.01(m, 2H); LC/MS (ESI+): 481.0 (M+H).

Example 486[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-o-tolyl-amine

This product was prepared from4-[2-(2-chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester according to a procedure similar to Example 481f:yellow foam; ¹H-NMR (CDCl₃) δ: 9.08 (s, 1H), 8.33 (d, J=5.2 Hz, 1H),8.02 (s, 1H), 7.81 (s, 1H), 7.76 (m, 1H), 7.60 (m, 1H), 7.24 (m, 2H),7.08 (m, 1H), 6.54 (br s, 1H), 3.72 (br s, 4H), 2.97 (m, 4H), 2.67 (m,1H), 3.04 (s, 3H), 1.95 (br s, NH), 1.25 (m, 2H), 0.99 (m, 2H);

LC/MS (ESI+): 438.1 (M+H).

Example 4872-{4-[5-Cyclopropyl-4-((3R,4S)-3,4-dihydroxy-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile

This product was obtained by separation of enantiomers (SCF chiralchromatography) of racemic Example 485.

Example 4882-{4-[5-Cyclopropyl-4-((3S,4R)-3,4-dihydroxy-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile

This product was obtained by separation of enantiomers (SCF chiralchromatography) of racemic Example 485. It is the optical antipode ofExample 487.

Example 4894-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-N-(1-phenylpyrazol-4-yl)pyridin-2-amine

A tube was charged with4-[2-(2-chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (131.4 mg, 0.2877 mmol),1-phenyl-1H-pyrazol-4-ylamine (55.0 mg, 0.346 mmol), Palladium Acetate(7.9 mg, 0.035 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene(21.0 mg, 0.0364 mmol), cesium carbonate (144.6 mg, 0.4438 mmol) and1,4-dioxane (1 mL). The tube was evacuated and back flushed withnitrogen. The tube was sealed and the reaction mixture was heated at 90°C. for 18 hours. The mixture was cooled to room temperature and dilutedwith water (10 mL). The suspension was stirred for 15 minutes, filtered,rinsed with water and dried by suction to yield a dark solid.

The dark solid was suspended in methylene chloride (3 mL) and stirred atroom temperature. Trifluoroacetic Acid (1 mL, 20 mmol) was addeddropwise and the mixture was stirred at room temperature for 1 hour. Thevolatiles were evaporated. The residue was purified via reverse phasechromatography using a Gilson apparatus with 5%→30% acetonitrile: water(w/ 0.1% TFA as modifier) solvent gradient. The desired fractions werecombined, frozen and lyophilized. The recovered lyophilate wasconsistent for desired4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-N-(1-phenylpyrazol-4-yl)pyridin-2-amine(14 mg, 10%). ¹H NMR (DMSO-d₆): δ-8.91 (bs, 1H), 8.71 (bs, 3H), 8.41 (s,1H), 8.34 (d, 1H, J=5.43 Hz), 7.88 (s, 1H), 7.84 (s, 1H), 7.83 (dd, 2H,JJ=1.09, 8.69 Hz), 7.66 (dd, 1H, JJ=1.30, 5.65), 7.47-7.53 (m, 2H),7.25-7.31 (m, 1H), 4.10 (s, 3H), 3.88 (bs, 4H), 3.33 (bs, 4H). LCMS(ESI+) 480.3 (M+H).

Example 490(2,3-Dimethyl-2H-indazol-6-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

A tube was charged with4-[2-(2-chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (131.4 mg, 0.2877 mmol),2,3-dimethyl-2H-indazol-6-ylamine (55.7 mg, 0.346 mmol), palladiumacetate (7.9 mg, 0.035 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (21.0 mg, 0.0364 mmol),cesium carbonate (144.6 mg, 0.4438 mmol) and 1,4-dioxane (1 mL). Thetube was evacuated and back flushed with nitrogen. The tube was sealedand the reaction mixture was heated at 90° C. for 18 hours. The mixturewas cooled to room temperature and diluted with water (10 mL). Thesuspension was stirred for 15 minutes, filtered, rinsed with water anddried by suction to yield a dark solid.

The dark solid was suspended in methylene chloride (3 mL, 40 mmol) andstirred at room temperature. Trifluoroacetic Acid (1 mL, 20 mmol) wasadded dropwise and the mixture was stirred at room temperature for 1hour. The volatiles were evaporated. The residue was purified viareverse phase chromatography using a Gilson apparatus with 5%-30%acetonitrile: water (w/0.1% TFA as modifier) solvent gradient. Thedesired fractions were combined, frozen and lyophilized. The recoveredlyophilate was consistent for desired(2,3-dimethyl-2H-indazol-6-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine (38 mg, 27%).

¹H NMR (DMSO-d₆): δ-9.50 9 bs, 1H), 8.91 (bs, 3H), 8.42 (s, 1H), 8.36(d, 1H, J=5.19 Hz), 8.24 (bs, 1H), 8.01 (bs, 1H), 7.72 (dd, 1H, J=1.20,5.28 Hz), 7.58 (d, 1H, J=9.07 Hz), 7.06 (dd, 1H, JJ=1.65, 8.87 Hz), 4.10(s, 3H), 3.99 (s, 3H0, 3.89 (bs, 4H), 3.33 (bs, 3H), 2.57 (s, 3H). LCMS(ESI+) 482.1 (M+H).

Example 491[1-(2-Fluoro-phenyl)-1H-pyrazol-4-yl]-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

A tube was charged with4-[2-(2-chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (131.4 mg, 0.2877 mmol),1-(2-fluoro-phenyl)-1H-pyrazol-4-ylamine (61.2 mg, 0.346 mmol),palladium acetate (7.9 mg, 0.035 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (21.0 mg, 0.0364 mmol),cesium carbonate (144.6 mg, 0.4438 mmol) and 1,4-dioxane (1 mL). Thetube was evacuated and backflushed with nitrogen. The tube was sealedand the reaction mixture was heated at 90° C. for 18 hours. The mixturewas cooled to room temperature and diluted with water (10 mL). Thesuspension was stirred for 15 minutes, filtered, rinsed with water anddried by suction to yield a dark solid. The dark solid was suspended inmethylene chloride (3 mL) and stirred at room temperature.Trifluoroacetic Acid (1 mL, 20 mmol) was added dropwise and the mixturewas stirred at room temperature for 1 hour. The volatiles wereevaporated. The residue was purified via reverse phase chromatographyusing a Gilson apparatus with 5%-*30% acetonitrile: water (w/ 0.1% TFAas modifier) solvent gradient. The desired fractions were combined,frozen and lyophilized. The recovered lyophilate was consistent fordesired[1-(2-fluoro-phenyl)-1H-pyrazol-4-yl]-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine (12 mg, 8.4%) ¹H NMR (DMSO-d₆):δ-9.51 (bs, 1H), 8.90 (bs, 3H), 8.59 (d, 1H, J=3.17 Hz), 8.41 (s, 1H),8.33 (d, 1H, J=5.50 Hz), 7.83-7.88 (m, 3H), 7.69 (dd, 1H, J=1.33, 5.50Hz), 7.33-7.51 (m, 3H), 4.10 (s, 3H), 3.88 (bs, 4H), 3.33 (bs, 4H). LCMS(ESI+) 490.1 (M+H). HPLC>95% pure (retaintion time=1.7 min. in Gmethod).

Example 492[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-phenyl-1H-pyrazol-4-yl)-amine

A tube was charged with4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (403.0 mg, 0.8631 mmol),1-Phenyl-1H-pyrazol-4-ylamine (165.0 mg, 1.036 mmol), Palladium Acetate(24 mg, 0.10 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene(63.1 mg, 0.109 mmol), Cesium Carbonate (433.8 mg, 1.331 mmol) and1,4-Dioxane (4 mL). The tube was evacuated and backflushed withnitrogen. The tube was sealed and the reaction mixture was heated at 90°C. for 18 hours. The mixture was cooled to room temperature and dilutedwith water (10 mL). The suspension was stirred for 15 minutes, filtered,rinsed with water and dried by suction to yield a dark solid.

The dark solid was suspended in methylene chloride (8 mL) and stirred atroom temperature. Trifluoroacetic Acid (4 mL, 50 mmol) was addeddropwise and the mixture was stirred at room temperature for 1 hour. Thevolatiles were evaporated. The residue was purified via reverse phasechromatography using a Gilson apparatus with 5%-*30% acetonitrile: water(w/ 0.1% TFA as modifier) solvent gradient. The desired fractions werecombined, frozen and lyophilized. The recovered lyophilate wasconsistent for desired[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-phenyl-1H-pyrazol-4-yl)-amine(10 mg, 4%).

¹H NMR (DMSO-d₆): δ-9.40 (s, 1H), 8.97 (s, 1H), 8.7 (s, 1H), 8.35 (d,1H, J=5.65 Hz), 8.09 (s, 1H), 7.78-7.85 (m, 4H), 7.63 (dd, 1H, J=1.42,5.34 Hz), 7.49 (t, 2H, J=8.37 Hz), 7.27 (t, 1H, J=7.48 Hz), 3.52-3.88(bm, 4H), 2.58-2.85 (bm, 5H), 1.20-1.32 (m, 2H), 1.00-1.06 (m, 2H). LCMS(ESI+) 490.19 (M+H). HPLC>95% pure (retaintion time=1.8 min. in Gmethod).

Example 493[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3-dimethyl-2H-indazol-6-yl)-amine

A tube was charged with4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (241.2 mg, 0.5166 mmol),2,3-Dimethyl-2H-indazol-6-ylamine (100.0 mg, 0.6203 mmol), PalladiumAcetate (14 mg, 0.063 mmol),9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (37.8 mg, 0.0653 mmol),Cesium Carbonate (259.6 mg, 0.7968 mmol) and 1,4-Dioxane (2 mL). Thetube was evacuated and backflushed with nitrogen. The tube was sealedand the reaction mixture was heated at 90° C. for 18 hours. The mixturewas cooled to room temperature and diluted with water (10 mL). Thesuspension was stirred for 15 minutes, filtered, rinsed with water anddried by suction to yield a brown solid. The dark solid was suspended inMethylene chloride (5 mL, 70 mmol) and stirred at room temperature.Trifluoroacetic Acid (2 mL, 30 mmol) was added dropwise and the mixturewas stirred at room temperature for 1 hour. The volatiles wereevaporated. The residue was purified via reverse phase chromatographyusing a Gilson apparatus with 5%-30% Acetonitrile: Water (w/0.1% TFA asmodifier) solvent gradient. The desired fractions were combined, frozenand lyophilized. The recovered lyophilate was consistent with[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3-dimethyl-2H-indazol-6-yl)-amine(60 mg, 24%).

¹H NMR (DMSO-d₆): δ-9.32 (s, 1H), 8.96 (s, 1H), 8.35 (d, 1H, J=5.25 Hz),8.28 (bs, 1H), 8.08 (s, 1H), 7.95 (bs, 1H), 7.68 (dd, 1H, J=1.36, 5.45Hz), 7.52 (d, 1H, J=8.95 Hz), 7.04 (dd, 1H, J=1.56, 8.95 Hz), 3.97 (s,3H), 2.53-2.70 (m, 5H), 2.45 (bs, 4H), 2.45 (s, 3H), 1.21-1.29 (m, 2H),1.00-1.06 (m, 2H). LCMS (ESI+) 492.20 (M+H). HPLC>95% pure (retaintiontime=1.7 min. in G method).

Example 494Phenyl-[4-(4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine

Following a procedure similar to 303c,4-[2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (180 mg, 0.42 mmol), and Aniline (51.1 uL, 0.561mmol) were converted to the title compound 35.28 mgs, 22% yield.LC/MS=384.2 (M+H)+

Example 495[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-pyridin-3-yl)-amine

A tube was charged with4-[2-(2-chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (100 mg, 0.214 mmol), 2-fluoro-pyridin-3-ylamine(46.2 mg, 0.412 mmol), palladium acetate (12.0 mg, 0.053 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (34.0 mg, 0.058 mmol),cesium carbonate (120 mg, 0.368 mmol) and 1,4-dioxane (0.7 mL, 8 mmol).The tube was evacuated and backflushed with nitrogen. The tube wassealed and the reaction mixture was heated at 100° C. for 3h. Themixture was cooled to room temperature and diluted with dichloromethane(10 mL) and filtered through celite. The filtrate was evaporated to adark resin.

The brown resin was dissolved in methylene chloride (0.7 mL, 10 mmol)and trifluoroacetic acid (0.7 mL, 9 mmol) was added. The mixture wasstirred for 1 hour at room temperature and concentrated. The residue waspurified via reverse phase chromatography using a Gilson apparatus. Thedesired fractions were loaded onto a SCX cartridge and rinsed withmethanol and the product was released with 2M ammonia in methanol. Theammonia filtrate was evaporated and placed under high vacuum for 2hours. The recovered yellow solid (35 mg, 37%) was consistent for thetitle compound. 1H NMR (300 MHz, DMSO-d6): 9.26 (s, 1H), 8.98 (s, 1H),8.88 (t, J=9 Hz, 1H), 8.34 (d, J=5 Hz, 1H), 8.18 (s, 1H), 8.10 (s, 1H),7.79 (d, J=5 Hz, 1H), 7.75 (d, J=4 Hz, 1H), 7.31 (m, 1H), 3.72 (m, 4H),2.88 (br s, 4H), 2.62 (m, 1H), 1.26 (d, J=8 Hz, 2H), 1.04 (d, J=5 Hz,2H), MS: 433 (M+H).

Example 496[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methyl-isoxazol-3-yl)-amine

4-[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (75 mg, 0.16 mmol), 5-methyl-isoxazol-3-ylamine(32.2 mg, 0.3283 mmol), bis(dibenzylideneacetone)palladium(0) (5 mg,0.0085 mmol), XANTPHOS (10 mg, 0.171 mmol), and lithiumhexamethylsilazide (55 mg, 0.328 mmol) were combined in tetrahydrofuran(3 mL), degassed with Argon and subjected to reaction in a microwave at120C for six hours. Additional palladium, isoxazole, and silazide wereadded and the microwave temperature was raised to 150C for an additionalsix hours. The reaction was concentrated and purification was effectedvia reverse phase chromatography to afford the title compound (2 mg,3%). MS: 419.23 (M+H).

Example 4972-[2-(3-Piperazin-1-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-ol

Following a procedure similar to Example 303c,2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol (67 mg, 0.26 mmol)and 4-(3-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester(1.1 eq) were converted to the title compound isolated as the bis-TFAsalt (21 mg, 13%). LC/MS: M+H+=400.

Example 4982-[2-(3-Piperazin-1-ylmethyl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-ol

Following a procedure similar to Example 303c,2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol (143 mg, 0.56mmol) and 4-(3-Amino-benzyl)-piperazine-1-carboxylic acid tert-butylester (1.1 eq) were converted to the title compound isolated as the bisTFA salt (51.4 mg, 14%). LC/MS: M+H+=414.

Example 4992-[2-(1-Piperidin-4-ylmethyl-1H-pyrazol-4-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-ol

Following a procedure similar to Example 303c,2-(2-Chloro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol (145 mg, 0.56mmol) and 4-(4-Amino-pyrazol-1-ylmethyl)-piperidine-1-carboxylic acidtert-butyl ester (1.1 eq) were converted to the title compound isolatedas the bis TFA salt (20.56 mg, 6%). LC/MS: M+H+=403.

Example 500{5-Methoxy-2-[2-(3-piperazin-1-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-amine

Following a procedure similar to Example 303b,2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol (362mgs, 1.25 mmol) and methylamine.HCl (1.1 eq) were converted to[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-methyl-amine(64% yield) which was converted using a procedure analogous to Example497 to the title compound islated as a bis TFA salt (14 mgs, 5% yield),LC/MS: M+H+=443.25

Example 501(5-Methoxy-2-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-methyl-amine

Following a procedure analogous to Example 500,4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (44 mg, 0.21 mmol) wasconverted to the title compound isolated as the bis-TFA salt (6.35 mgs,5% yield) LC/MS: M+H+=472.

Example 502{5-Methoxy-2-[2-(3-piperidin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-amine

Following a procedure analogous to Example 500,4-(3-Amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.1468g, 0.5312 mmol) was converted to the title compound isolated as abis-TFA salt (23.61 mgs, 7% yield). LC/MS: M+H+=442.

Example 503[4-(5-Methoxy-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-piperazin-1-yl-phenyl)-amine

503a) 2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol(208 mg, 0.720 mmol), 2,4,6-Triisopropylbenzenesulfonyl Chloride (221.1mg, 0.7301 mmol), Triethylamine (0.31 mL, 2.2 mmol), and4-Dimethylaminopyridine (8.8 mg, 0.072 mmol) in N,N-Dimethylformamide (2mL, 30 mmol) were stirred at room temperature for 1 h, Hydrazine hydrate(0.05410 g, 1.081 mmol) was added and the reaction was stirredovernight. The product precipitated and was triturated from ether.Taking on without further purification.

503b)[2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl]-hydrazine(0.218 g, 0.720 mmol) was treated with 1,4-Dioxane (5.0 mL, 65 mmol) andWater (0.6 mL, 30 mmol) and then Silver(I) Oxide (334 mg, 1.44 mmol) andstirred at room temperature. After 1.5 h, LC/MS indicated major product(M+H)+=273. Filtered off silver salts and concentrated and put on highvac. Purified by ISCO chomatography 12 g SiO2, gradient elution 0% to100% EA/hexane over 13 minutes to give2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidine 503c) Usinga procedure analogous to Example 497 to the title compound2-(2-Chloro-pyridin-4-yl)-5-methoxy-pyrido[3,4-d]pyrimidine (31 mgs,0.11 mmol) was converted to the title compound (6.37 mgs, 13% yield).LC/MS: M+H+=414.

The following compounds were synthesised according to the generalsynthesis shown in scheme [B4]

Analysis Ex Amine 1 Amine 2 LCMS NMR Name 504

method 5: RT: 2.87 min, MI: 456 [M + H] 1H NMR (DMSO, 500 MHz) 9.04 (1H,s), 8.30 (1H, d), 8.17 (1H, s), 8.05 (1H, s), 7.94 (1H, d), 7.73 (1H,d), 7.13 (1H, d), 6.87 (1H, m), 3.90 (4H, very broad s), 3.31 (4H, 1HNMR (DMSO, 500 MHz) 9.04 (1H, s), 8.30 (1H, d), 8.17 (1H, s), 8.05 (1H,s), 7.94 (1H, d), 7.73 (1H, d), 7.13 (1H, d), 6.87 (1H, m), 3.90 (4H,[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(2- fluoro-5-methyl- phenyl)- amine very broad s), 3.31(4H, broad s), 2.68 (1H, m), 2.29 (3H, s), 1.25 (2H, m), 1.06 (2H, m).505

method 5: RT: 2.20 min, MI: 452 [M + H] 1H NMR (DMSO, 500 MHz) 9.07 (1H,s), 8.19 (1H, s), 8.14 (1H, d), 7.98 (1H, s), 7.73 (1H, d), 7.33 (1H,s), 7.22 (1H, d), 7.03 (1H, d), 3.89 (4H, very broad s), 3.30 (4H, 1HNMR (DMSO, 500 MHz) 9.07 (1H, s), 8.19 (1H, s), 8.14 (1H, d), 7.98 (1H,s), 7.73 (1H, d), 7.33 (1H, s), 7.22 (1H, d), 7.03 (1H, d), 3.89 (4H,[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(2,5- dimethyl-phenyl)- amine very broad s), 3.30 (4H,broad s), 2.48 (1H, m), 2.29 (3H, s), 2.20 (3H, s), 1.25 (2H, m), 1.07(2H, m) 506

method 5: RT: 5.19 min, MI: 450 [M + H] NMR: (DMSO) 10.27 ppm (s, 1H),9.06 ppm (s, 1H), 8.95 ppm (d, 1H), 8.58 ppm (dd, 1H), 8.48 ppm (d, 1H),8.19 ppm (s, 1H), 8.06 ppm (s, 1H), 7.91 ppm (m, 2H), 3.85 ppm (s, 4H),3.90 ppm (broad s, 4H), 2.68 ppm (m, 1H), 1.27 ppm (m, 2H), 1.09 ppm (m,2H). A second set of piperazine 4H is suspected to be running under the5-[4-(5- Cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2- ylamino]-pyridine- 2-carbonitrile DMSO water peak at 3.33ppm. 507

method 5: RT: 2.10 min, MI: 426 [M + H] 1H NMR (DMSO, 500 MHz) 9.08 (1H,s), 8.78 (1H, s), 8.47 (1H, d), 8.31 (1H, m), 8.19 (1H, s), 8.16 (1H,d), 7.94 (2H, dd), 3.93 (4H, very broad s), 3.31 (4H, br s), 2.68 (1H,m), 1.26-1.24 (2H, m), 1.08- 1.05 (2H, m). 4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-pyrazin-2-yl-amine 508

method 5: RT 3.28 min, MI: 456.17 [M + H] 1H NMR (DMSO, 500 MHz) 8.99(1H, s), 8.15 (1H, d), 8.10 (1H, s), 7.64 (1H, s), 7.49 (1H, d), 6.98(1H, s), 4.56-4.25 (1H, m, br), 3.95 (1H, d, br), 3.65 (s, br, 4H), 3.03(4H, s, br), 1.28-1.22 (3H, m, br), 1.05-1.01 2H, m, br), 0.73 (2H, d,br), 0.47 (2H, s, br). Cyclopropyl-{4-[5- cyclopropyl-4-(3-trifluoromethyl- piperazin-1-yl)- pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2- yl}-amine 509

method 5: RT 1.73 min:, MI: 418.19 [M + H] 1H NMR (DMSO, 500 MHz) 8.99(1H, s), 8.13 (1H, d), 8.12 (1H, s), 7.58 (1H, s), 7.45 (1H, d), 7.05(1H, d), 4.43 (1H, m, br), 3.91-3.82 (2H, m), 3.80 (4H, m, br),3.75-3.70 1H NMR (DMSO, 500 MHz) 8.99 (1H, s), 8.13 (1H, d), 8.12 (1H,s), 7.58 (1H, s), 7.45 (1H, d), 7.05 (1H, d), 4.43 (1H, m, br),3.91-3.82 (2H, m), [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(R)- tetrahydro-furan-3- yl-amine 3.80(4H, m, br), 3.75-3.70 (1H, m), 3.54 (1H, dd), 3.20 (4H, m, br),2.70-2.67 (1H, m), 2.21-2.14 (1H, m), 510

method 5: RT: 2.37 min, MI: 466.20 [M + H] 1H NMR (500 MHz, DMSO) 8.93(1H, s), 8.11 (1H, d), 8.06 (1H, s), 7.54 (1H, s), 7.41 (1H, d), 6.80(1H, d), 4.02-3.97 (1H, m, br), 3.79-3.54 (4H, m, br), 2.84 (4H, m, 2.621H NMR (500 MHz, DMSO) 8.93 (1H, s), 8.11 (1H, d), 8.06 (1H, s), 7.54(1H, s), 7.41 (1H, d), 6.80 (1H, d), 4.02-3.97 (1H, m, br), 3.79-3.54[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(4,4- difluoro- cyclohexyl)-amine (4H, m, br), 2.84 (4H,m, 2.62-2.59 (1H, m), 2.10-1.89 (6H, m, br), 1.59-1.53 (2H, m, br),1.26-1.22 (2H, m), 1 511

method 5: RT: 2.31 min, MI: 525 [M + H] 1H NMR (DMSO, 500 MHz) 9.00 (1H,s), 8.68 (1H, s), 8.50 (1H, m), 8.45 (1H, m), 8.32 (1H, m), 8.11 (1H,s), 7.89 (1H, d), 7.85 (1H, m), 4.47 (1H, d), 4.38 (1H, d), 4.30 (1H,m), 4.16 (1H, m), 3.32 (1H, m), 3.22 (2H, m), 3.13 (2H, m), 2.62 (1H,m), 1.26-1.24 (2H, m), 1.05-1.03 (2H, {4-[5-Cyclopropyl-4-((R)-3-fluorometh- yl-piperazin-1- yl)-pyrido[3,4-d]py- rimidin-2-yl]-pyridin-2-yl}-(4- trifluoromethyl- pyridin-2-yl)- m) amine 512

method 5: RT: 2.31 min, MI: 525 [M + H] 1H NMR (DMSO, 500 MHz) 9.00 (1H,s), 8.68 (1H, s), 8.50 (1H, m), 8.45 (1H, m), 8.32 (1H, m), 8.11 (1H,s), 7.89 (1H, d), 7.85 (1H, m), 4.47 (1H, d), 4.38 (1H, d), 4.30 (1H,m), 4.16 (1H, m), 3.32 (1H, m), 3.22 (2H, m), 3.13 (2H, m), 2.62 (1H,m), {4-[5-Cyclopropyl- 4-((R)-3-fluorometh- yl-piperazin-1-yl)-pyrido[3,4-d]py- rimidin-2-yl]- pyridin-2-yl}-(6- fluoro-pyridin-2-1.26-1.24 (2H, m), 1.05-1.03 (2H, yl)-amine m) 513

455.2 (M + H) (CDCl₃) 9.12 (d, J = 1.6 Hz, 1H), 8.70 (dd, J = 8.0; 1.5Hz, 1H), 8.40 (d, J = 4.4 Hz, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.83 (dd,J = 5.2; 1.3 Hz, 1H), 7.75 (m, 1H), 7.19 (s, 1H), 6.92 (m, 1H), 4.07 (s,3H), 3.77 (br s, 4H), 3.04 (m, 4H), 2.70 (m, 1H), 1.84 (exch. protos),1.27 (m, 2H), 1.01 (m, 2H) [4-(5-Cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(2- methoxy-pyridin-3-yl)-amine 514

459.1 (M + H) (dmso-d6) 10.24 (s, 1H), 8.98 (s, 1H), 8.75 (s, 1H), 8.41(d, J = 5.2 Hz, 1H), 8.10 (s, 1H), 7.88 (m, 1H), 7.82 (m, 1H), 7.74 (m,1H), 6.97 (d, J = 7.5 Hz, 1H), 3.75 (br m, 4H), 2.86 (br m, 4H), 2.62(m, 1H), 1.25 (m, 2H), 1.03 (m, 2H) (6-Chloro-pyridin-2-yl)-[4-(5-cyclo- propyl-4-piperazin- 1-yl-pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- amine 515

454.2 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- methoxy-phenyl)- amine 516

492.1 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- trifluoromethyl- phenyl)- amine 517

468.2 (M + H)+ (CDCl₃) 9.11 (s, 1H), 8.37 (dd, J = 5.3; 0.4 Hz, 1H),8.04 (s, 1H), 7.96 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.79 (dd, J = 5.3;1.3 Hz, 1H), 7.72 (br s, 1H), 7.35 (m, 1H), 7.27 (m, 1H), 7.01 (m, 1H),4.57 (s, 2H), 3.75 (br s, 4H), 3.43 (s, 3H), 3.01 (m, 4H), 2.69 (m, 1H),2.04 (br s, esch. protons), 1.26 (m, 2H), 1.00 (m, 2H)[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(2- methoxymethyl- phenyl)-amine 518

method 5: RT: 2.27 min, MI: 418.17 M + H] 1H NMR (500 MHz, DMSO) 8.93(1H, s), 8.11 (1H, d), 8.06 (1H, s), 7.56 (1H, s), 7.43 (1H, dd), 7.01(1H, d), 4.45-4.39 (1H, m), 3.90- 3.53 (4H, s, br), 3.89 (1H, dd), 3.85(1H, q), 3.75-3.70 (1H, m), 3.55 (1H, dd), 3.15 (2H, d), 2.85 (4H, s,br), 2.62-2.61 (1H, m), 2.20-2.16 (1H, m), 1.85-1.80 (1H, m), 1.26-[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(S)- tetrahydro-furan-3- yl-amine 1.22 (2H, m), 1.02-1.01(2H, m) 519

449.1 (M + H)+ (CDCl₃) 9.14 (m, 2H), 8.42 (d, J = 1.4 Hz, 1H), 8.07 (s,1H), 7.93 (d, J = 8.1 Hz, 1H), 7.84 (dd, J = 8.1; 5.9 Hz, 1H), 7.68 (m,2H), 7.39 (m, 2H), 3.82 (m, 4H), 3.05 (m, 4H), 2.71 (m, 1H), 1.7 (br s,exch. H's), 1.28 (m, 2H), 1.02 (m, 2H) 2-[4-(5- Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2- ylamino]-benzonitrile 520

method 5: RT: 3.73 min, MI: 404.30 [M + H] 1H NMR (DMSO, 500 MHz) 8.92(1H, s), 8.07 (2H, dd), 7.56 (1H, s), 7.35 (1H, s), 6.47 (1H, s),3.75-3.54 (4H, m, br), 2.83 (4H, m, br), 2.62 (1H, m, br), 1.41 (9H, s),1.24 (2H, m, br), 1.00 (2H, m, br). tert-Butyl-[4-(5- cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2- yl)-pyrido-2-yl]- amine 521

method 5: RT: 3.90 min, MI: 460 [M + H] 1H NMR (DMSO, 500 MHz) 9.25 (1H,s), 9.05 (1H, s), 8.97 (1H, s, br), 8.39 (1H, d), 8.24 (1H, s), 8.17(1H, s), 7.78 (1H, d), 7.28 (1H, m), 6.76 (1H, m), 3.96-3.88 (4H, s,br), 3.31 (4H, s, br), 2.65 (1H, m), 1.28-1.25 (2H, m), 1.08-1.05 (2H,m) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(2,5- difluoro-phenyl)- amine 522

method 5: RT: 4.02 min, MI: 510 [M + H] 1H NMR (DMSO, 500 MHz) 9.37 (1H,s), 9.06 (1'H, s), 8.97 (1H, s, br), 8.41 (1H, d), 8.23 (1H, s), 8.18(1H, s), 7.84 (1H, d), 7.47 (1H, m), 7.32 (1H, m), 3.96-3.88 (4H, s,br), 3.31 (4H, s, br), 2.65 (1H, m), 1.28-1.25 (2H, m), 1.08-1.05 (2H,m). [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(2- fluoro-5- trifluoromethyl- phenyl)-amine 523

method 5: RT: 3.80 min, MI: 466 [M + H] 1H NMR (DMSO, 500 MHz) 9.05 (1H,s), 8.97 (1H, s, br), 8.28 (1H, d), 8.18 (1H, s), 8.05 (1H, s), 7.81(1H, s), 7.75 (1H, d), 7.23 (1H, d), 6.81 (1H, d), 3.96-3.88 (4H, s,br), 3.31 (4H, s, br), 2.66 (1H, m), 2.27 (3H, s), 1.28-1.25 (2H, m),1.08- 1.05 (2H, m) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(5- fluoro-2-methyl- phenyl)- amine 524

1H NMR (DMSO, 500 MHz) 9.06 (1H, s), 8.96 (1H, s, br), 8.78 (1H, s),8.36 (1H, s), 8.33 (1H, d), 8.18 (1H, s), 8.06 (1H, s), 7.78 (1H, d),7.43 (1H, m), 3.96-3.88 (4H, s, br), 3.31 (4H, s, br), 2.68 (1H, m),2.38 (3H, s), 1.28-1.25 (2H, m), 1.08- 1.05 (2H, m) 3-[4-(5-Cyclopropyl-4- piperaizn-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-ylamino]-4-methyl- benzonitrile 525

method 5: RT: 3.20 min, MI: 480 [M + H] 1H NMR (DMSO, 500 MHz) 9.30 (1H,s), 9.01 (1H, s), 8.32 (1H, d), 8.16 (1H, s), 7.91 (1H, s), 7.75 (1H,d), 7.70 (1H, d,), 7.28 (2H, m), 6.90 (1H, m), 4.43 (4H, m), 4.05 (2H,m), 3.67 (1H, m), 3.48 (1H, m), 3.21 (1H, m), 2.53 (1H, m), 1.28-1.25(2H, m), 1.3-1.01 (2H, m) 7-[5-Cyclopropyl- 2-(2-phenylamino- pyri-din-4-yl)- pyrido[3,4- d]pyrimidin- 4-yl]-hexahydro- oxazolo[3,4-a]pyrazin-3-one 526

method 5: RT: 2.33 min, MI: 443 [M + H] 1H NMR (DMSO, 500 MHz) 11.53(1H, s), 9.11 (1H, s), 8.92 (1H, s), 8.55 (1H, d), 8.30 (1H, d), 8.24(1H, s), 8.21 (1H, dd), 7.98 (1H, m), 7.31 (1H, m), 4.01 (4H, s), 3.30(4H, s), 2.68 (1H, m), 1.28 (2H, m), 1.10 (2H, m). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(3-fluoro- pyridin-2-yl)- amine 527

method 5: RT: 5.3 min, MI: 472 [M + H] 1H NMR (DMSO, 500 MHz, 1IGO538)9.05 (1H, s), 9.02-8.90 (2H, broad s), 8.19 (1H, s), 8.14 (1H, d), 7.75(1H, s), 7.69 (1H, d), 7.45 (1H, d), 7.34 (1H, d), 7.27 (1H, m), 3.89(4H, s), 3.31 (4H, s), 2.67 (1H, m), 1.26 (2H, m), 1.07 (2H, m)(2-Chloro-6- methyl-phenyl)-[4- (5-cyclopropyl-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin-2- yl)-pyridin-2-yl]- amine 528

method 5: RT: 3.68 min, MI: 467 [M + H] 1H NMR (DMSO, 500 MHz, 1IGO539)9.41 (1H, s), 9.05 (1H, s), 8.98 (1H, d), 8.43 (1H, d), 8.23 (1H, s),8.18 (1H, s), 7.86 (1H, d), 7.49 (1H, m), 3.94 (4H, s), 3.33 (4H, s),2.69 (1H, m), 1.26 (2H, m), 1.08 (2H, m). 3-[4-(5- Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-ylamino]-4-fluoro- benzonitrile 529

method 5: RT: 4.21 min, MI: 514 [M + H] 1H NMR (DMSO, 500 MHz, 1IGO541)9.06 (1H, s), 9.01-8.90 (2H, broad s), 8.24 (1H, d), 8.19 (1H, s), 8.01(1H, s), 7.84 (1H, d), 7.75 (1H, dd), 7.48 (1H, d), 7.39 (1H, dd), 3.91(4H, s), 3.32 (4H, s), 2.68 (1H, m), 1.31 (9H, s), 1.24 (2H, m), 1.08(2H, m). (4-tert-Butyl-2- chloro-phenyl)-[4- (5-cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2- yl]-amine 530

method 5: RT: 2.13 min, MI: 482 [M + H] 1H NMR (DMSO, 500 MHz) 10.00(1H, s), 9.06 (1H, s), 8.61 (1H, s), 8.48 (2H, m), 8.31 (1H, s), 7.93(1H, d), 7.26 (1H, d), 4.44 (2H, m), 4.06 (2H, m), 3.77 (1H, m), 3.35(4H, m), 2.68 (1H, m), 1.28-1.25 (2H, m), 1.02-0.99 (2H, m) 2-[4-[5-Cyclopropyl-4- ((R)-3-fluoro methyl-piperazin- 1-yl)-pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-ylamino}- isonicotinonitrile 531

method 5: RT: 2.54 min, MI: 475 [M + H] 1H NMR (DMSO, 500 MHz) 9.22 (1H,s), 8.98 (1H, s), 8.86 (1H, m), 8.33 (1H, d), 8.15 (1H, s), 8.13 (1H,s), 8.11 (1H, s), 7.79 (1H, d), 7.74 (1H, d), 7.30 (1H, m), 4.50 (1H,d), 4.40 (1H, d), 4.17 (1H, m), 3.34 (2H, m), 3.21 (2H, m), 2.99 (2H,m), {4-[5-Cyclopropyl- 4-((R)-3-fluorometh- yl-piperazin-1-yl)-pyrido[3,4-d]pyri- midin-2-yl]- pyridin-2-yl}-(2- fluoro-pyridin-3-2.53 (1H, m), 1.26-1.24 (2H, m), yl)-amine 1.05-1.03 (2H, m). 532

method 5: RT: 2.75 min, MI: 430.26 [M + H] 1H NMR (DMSO, 500 MHz) 8.94(1H, s), 8.16 (1H, d), 8.07 (1H, s), 7.8 (1H, s), 7.54 (1H, dd), 7.40(1H, t), 4.24-4.20 (2H, m), 3.86-3.51 (4H, m, br), 2.84 (4H, m, br),2.63- 2.57 (1H, m), 1.25-1.23 (2H, m), 1.02-1.01 (2H, m).[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- (2,2,2-trifluoro- ethyl)-amine 533

method 5: RT: 2.99 min, MI: 506 [M + H] 1H NMR (DMSO, 500 MHz) 10.00(1H, s), 9.06 (1H, s), 8.61 (1H, s), 8.48 (2H, m), 8.31 (1H, s), 7.93(1H, d), 7.26 (1H, d), 4.44 (2H, m), 4.06 (2H, m), 3.77 (1H, m), 3.35(4H, m), 2.68 (1H, m), 1.28-1.25 (2H, m), 1.02-0.99 (2H, m) 2-{4-[5-Cyclopropyl-4-(3- oxo-tetrahydro- oxazolo[3,4- a]pyrazin-7-yl)-py-rido[3,4- d]pyrimidin-2-yl]- pyridin- 2-ylamino}- isonicotinonitrile 534

method 5: RT: 3.4 min, MI: 493 [M + H] [4-(5-cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(6-trifluoromethyl- pyridin- 2-yl)-amine 535

method 5: RT: 3.81 min, MI: 443 [M + H] 1H NMR (DMSO, 500 MHz, 1IGO528)9.90 (1H, s), 8.98 (1H, s), 8.59 (1H, t), 8.48-8.44 (1H, td), 8.42 (1H,d), 8.20 (1H, s), 8.07 (1H, d), 7.98 (1H, s), 7.82 (1H, dd), 2.89 (4H,s), 2.63 (1H, m), 1.27 (2H, m), 1.40 (2H, m). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(5-fluoro-pyridin-3- yl)-amine 536

method 5: RT: 3.31 min, MI: 493 [M + H] 1H NMR (DMSO, 500 MHz, 1IGO529)8.98 (1H, s), 8.83 (1H, s), 8.44 (1H, d), 8.28 (1H, d), 8.20 (1H, d),8.10 (1H, s), 8.04 (1H, s), 7.75 (1H, d), 7.69-7.66 (1H, q), 3.42 (4H,broad s), 2.87 (1H, s), 2.62 (1H, m), 1.27 (2H, m), 1.04 (2H, m).[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(2- trifluoromethyl- pyridin-3-yl)- amine 537

436.1 {4-[5-Cyclopropyl- 4-(2,5-diaza-bicy- clo[4.1.0]hept-2-yl)-pyrido[3,4-d]py- rimidin-2-yl]- pyridin-2-yl}- phenyl-amine 538

472.1 {4-[5-Cyclopropyl- 4-(2,5-diaza-bicy- clo[4.1.0]hept-2-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6- difluoro-phenyl)-amine 539

492.1 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,6- dichloro-phenyl)- amine 540

452.2 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,3- dimethyl-phenyl)- amine 541

452.2 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,6- dimethyl-phenyl)- amine 542

492.1 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,3- dichloro-phenyl)- amine 543

466.30 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,3- dichloro-phenyl)- amine 544

439.20 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- methyl-pyridin-3- yl)-amine 545

426.15 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- pyridazin-3-yl- amine 546

439.20 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(6- methyl-pyridin-3- yl)-amine 547

455.20 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(6- methoxy-pyridin-3- yl)-amine 548

461.20 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3,6- difluoro-pyridin-2- yl)-amine 549

500.20 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[4- (dimethyl- phosphinoyl)-phenyl]-amine 550

528.20 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[4- (diethyl- phosphinoyl)-phenyl]-amine 551

468.25 (M + H) N⁵-[4-(5- Cyclopropyl-4- piperazin- 1-yl-pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- N²,N²-dimethyl- pyridine-2,5- diamine552

method 5: RT: 2.16 min, MI: 456 [M + H] 1H NMR (DMSO, 500 MHz) 9.30 (1H,s), 8.98 (1H, s), 8.31 (1H, d), 8.11 (1H, s), 7.90 (1H, s), 7.75 (1H,d), 7.66 (1H, d), 7.27 (2H, m), 6.89 (1H, m), 4.46 (1H, d), 4.38 (1H,d), 4.13 (2H, m), 3.34 (2H, m), 3.00 (3H, m), 2.68 (1H, m), 1.28-1.25(2H, m), 1.08-1.05 (2H, m) {4-[5-Cyclopropyl- 4-((R)-3-fluoro-methyl-piperazin-1- yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-phenyl-amine 553

method 5: RT: 3.74 min, MI: 468 [M + H] 1H NMR (DMSO, 500 MHz) 9.05 (1H,s), 8.91 (1H, s, br), 8.19 (2H, dd), 7.97 (1H, s), 7.72 (1H, d), 7.26(1H, s), 7.21 (1H, dd), 6.73 (1H, d), 3.99-3.88 (4H, s, br), 3.73 (3H,s), 3.30 (4H, s, br), 2.62 (1H, m, br), 2.19 (3H, s), 2.20 (3H, s),1.25-1.23 (2H, m), 1.08-1.05 (2H, m). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(5-methoxy-2-methyl- phenyl)- amine 554

method 5: RT: 2.92 min, MI: 405 [M + H] 1H NMR (DMSO, 500 MHz) 9.05 (1H,s), 8.98 (1H, s, br), 8.28 (1H, dd), 8.22 (1H, s), 8.18 (1H, s), 8.06(1H, s), 7.78 (1H, d), 7.49 (1H, d), 7.36 (1H, d), 3.96-3.88 (4H, s,br), 3.30 (4H, s, br), 2.68 (1H, m), 2.37 (3H, s), 1.26-1.23 (2H, m),1.08- 1.05 (2H, m) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- methyl-5- trifluoromethyl-phenyl)-amine 555

method 5: RT: 3.30 min, MI: 526 [M + H] 1H NMR (DMSO, 500 MHz) 9.32 (1H,s), 9.05 (1H, s), 8.92 (1H, s, br), 8.62 (1H, m), 8.40 (1H, d), 8.23(1H, s), 8.18 (1H, s), 8.06 (1H, s), 7.83 (1H, d), 7.49 (1H, d), 7.36(1H, m), 3.96-3.88 (4H, s, br), 3.33 (4H, s, br), 2.68 (1H, m),1.26-1.23 (2H, m), 1.08-1.05 (2H, m). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(2-fluoro-5- trifluoromethoxy- phenyl)-amine 556

method 5: RT: 2.35 min, MI: 520 [M + H] 1H NMR (DMSO, 500 MHz) 9.44 (1H,s), 9.08 (1H, s), 9.04 (1H, s), 8.97 (1H, s, br), 8.43 (1H, dd), 8.24(1H, s), 8.20 (1H, s), 7.87 (1H, d), 7.56 (1H, d), 3.96-3.88 (4H, s,br), 3.35 (4H, s, br), 3.24 (3H, s), 2.69 (1H, m), 1.28-1.25 (2H, m),1.08- 1.05 (2H, m). [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- fluoro-5- methanesulfonyl-phenyl)-amine 557

method 5: RT: 2.37 min, MI: 474 [M + H] H NMR (DMSO, 500 MHz) 9.05 (1H,s), 8.93 (1H, s, br), 8.83 (1H, s), 8.18 (1H, s), 7.82 (1H, s), 7.15(1H, m), 7.06 (1H, m), 3.87 (4H, s, br), 3.31 (4H, s, br), 2.69 (1H, m),2.24 (3H, s), 1.26-1.24 (2H, m), 1.07- 1.05 (2H, m). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(2,6-difluoro-3-methyl- phenyl)-amine 558

method 5: RT: 4.08 min, MI: 480 [M + H] 1H NMR (DMSO, 500 MHz) 9.02 (1H,s), 8.93 (1H, s, br), 8.17 (2H, dd), 7.90 (1H, s), 7.71 (1H, s), 7.38(1H, s), 7.23 (1H, dd), 7.02 (1H, m), 4.02-3.88 (4H, s, br), 3.30 (4H,s, br), 2.87 (1H, m, br), 2.63-2.57 (1H, m), 2.20 (3H, s), 1.25-1.23(2H, m), 1.20 (6H, m), 1.06-1.02 (2H, m) [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(5-isopropyl-2- methyl-phenyl)- amine 559

method 5: RT: 2.01 min, MI: 429 [M + H] 1H NMR (DMSO, 500 MHz) 9.45 (1H,s, br), 9.05 (1H, s), 8.90 (1H, s, br), 8.32 (1H, d), 8.18 (1H, s), 7.82(1H, s), 7.15 (1H, m), 7.06 (1H, m), 3.87 (4H, s, br), 3.31 (4H, s, br),2.69 (1H, m), 2.24 (3H, s), 1.26-1.24 (2H, m), 1.07-1.05 (2H, m).[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-pent- deuterio-phenyl- amine 560

450.2 (M − OH)+ (CDCl₃) 9.07 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 8.00 (brs, 2H), 7.91 (s, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.75 (dd, J = 5.3; 1.2Hz, 1H), 7.30 (m, 2H), 7.05 (m, 1H), 5.09 (q, J = 6.6 Hz, 1H), 3.73 (brs, 4H), 2.97 (m, 4H), 2.66 (m, 1H), 2.17 (br s, OH, exch. NH), 1.61 (d,J = 6.6 Hz, 3H), 1.24 (m, 2H), 0.98 (m, 2H) 1-{2-[4-(5- Cyclopropyl-4-piperazin- 1-yl-pyrido[3,4- d]pyimidin-2-yl)- pyridin-2-ylamino]-phenyl}- ethanol 561

459.25 (M + H)+ (dmso-d6; note: a minor rotamer also observed) 10.85 (s,1H), 9.17 (br s, exch. 3H), 9.08 (s, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.19(s, 1H), 8.10 (dd, J = 5.2; 1.4 Hz, 1H), 8.04 (br s, 3H), 4.19 (br s,large exch. H's signal), 3.91 (m, 4H), 3.35 (br s, 4H), 3.08 (m, 1H),2.70 (m, 1H), (1R, 2S)-2-Amino- cyclopentane- carboxylic acid [4-(5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- 2.24 (m, 1H), 2.08 (m, 2H), 1.73 amide (m, 4H), 1.26 (m,2H), 1.08 (m, 2H) 562

— 423.00 (M + H) 1-{4-[2-(2-Chloro- pyridin-4-yl)-5- cyclopropyl-pyrido[3,4- d]pyrimidin-4- yl]-piperazin-2- yl}-cyclopropanol 563

464.20 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- pyrazolo[1,5- a]pyridin-6-yl- amine564

464.15 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- pyrazolo[1,5- a]pyridin-5-yl- amine565

494.10 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(5- trifluoromethyl- pyridazin-3-yl)-amine 566

490 (dmso-d6) 9.11 (br s, 3H, exch. H's), 9.07 (s, 1H), 8.20 (m, 2H),7.88 (s, 1H), 7.73 (dd, J = 5.3; 1.4 Hz, 1H), 7.09 (m, 2H), 3.92 (br s,4H), 3.87 (s, 3H), 3.33 (br s, 4H), 2.69 (m, 1H), 1.26 (m, 2H), 1.09 (m,2H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6- difluoro-3- methoxy-phenyl)- amine 567

503.9 (dmso-d6) 9.06 (s, 1H), 9.05 (br s, 3H, exch. H's), 8.20 (m, 2H),7.87 (s, 1H), 7.72 (dd, J = 5.4; 1.3 Hz, 1H), 7.07 (m, 2H), 5.40 (br s,exch. H's), 4.12 (q, J = 7.0 Hz, 2H), 3.93 (br s, 4H), 3.33 (br s, 4H),2.68 (m, 1H), 1.36 (t, J = 7.0 Hz, 3H), 1.26 (m, 2H), 1.09 (m, 2H)[4-(5-Cyclopropyl- 4-piperazin--1yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(3- ethoxy-2,6- difluoro-phenyl)- amine 568

method 5: RT: 3.46 min, MI: 472 [M + H] 1H NMR (DMSO, 500 MHz), 9.06(1H, s), 8.26 (1H, d), 8.18 (1H, s), 8.05 (1H, s), 7.84 (1H, d), 7.75(1H, dd), 7.24 (1H, t), 7.11 (1H, s), 3.91 (4H, s), 3.32 (4H, s), 2.68(1H, m), 2.39 (3H, s), 1.25 (2H, m), 1.08 (2H, m). (2-Chloro-3-methyl-phenyl)-[4- (5-cylcopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2- yl)-pyridin-2-yl]- amine 569

method 5: RT: 4.22 min, MI: 438.28 [M + H] 1H NMR (DMSO, 500 MHz) 9.59(1H, br s), 9.05 (1H, s), 8.99 (1H, br s), 8.31 (1H, d), 8.18 (1H, s),7.97 (1H, s), 7.73-7.69 (2H, m), 7.32 (2H, t), 6.77 (1H, t), 4.96 (4H,br s), 4.32 (1H, br s), 3.37 (2H, br s), 1.34-1.23 (5H, m), 1.07 (2H, brs). {4-[5-Cycopropyl- 4-((S)-3-methyl- piperazin-1-yl)- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}- phenyl-amine 570

method 5: RT: 5.57 min, MI: 476 [M + H] 1H NMR (DMSO, 500 MHz),) 9.07(1H, s), 8.25 (1H, d), 8.19 (1H, s), 8.01 (1H, s), 7.93 (1H, m), 7.76(1H, d), 7.54 (1H, dd), 7.26 (1H, m), 3.92 (4H, s), 3.32 (4H, s), 2.68(1H, m), 1.24 (2H, m), 1.09 (2H, m). (2-Chloro-4-fluoro- phenyl)-[4-(5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- amine 571

method 5: RT: 5.27 min, MI: 454 [M + H] 1H NMR (DMSO, 500 MHz,) 9.53(1H, s), 9.06 (1H, s), 8.33 (1H, d), 8.19 (1H, s), 7.98 (1H, s), 7.74(1H, dd), 7.46 (1H, s), 7.24 (2H, m), 6.56 (1H, d), 3.91 (4H, s), 3.76(3H, s), 3.33 (4H, s), 2.69 (1H, m), 1.25 (2H, m), 1.08 (2H, m).[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(3- methoxy-phenyl)- amine 572

method 5: RT: 5.77 min, MI: 472 [M + H] 1H NMR (DMSO, 500 MHz,) 9.07(1H, s), 8.22 (1H, d), 8.19 (1H, s), 8.03 (1H, s), 7.76 (1H, dd), 7.46(1H, s), 7.74 (1H, d), 7.40 (1H, s), 7.20 (1H, d), 3.93 (4H, s), 3.32(4H, s), 2.66 (1H, m), 2.33 (3H, s), 1.25 (2H, m), 1.08 (2H, m).(2-Chloro-4- methyl-phenyl)-[4- (5-cyclopropyl-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin-2- yl)-pyridin-2-yl]- amine 573

452.0 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,4- dimethyl-phenyl)- amine 574

455.9 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- fluoro-3-methyl- phenyl)-amine 575

455.9 (MH)+ [4-(5-Cylcopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- fluoro-4-methyl- phenyl)-amine 576

method 5: RT: 4.02 min, MI: 476 [M + H] 1H NMR (DMSO, 500 MHz,) 9.07(1H, s), 8.87 (1H, s), 8.39 (1H, d), 8.23 (2H, m), 8.19 (1H, s), 7.85(1H, dd), 7.51 (1H, m), 6.88 (1H, m), 3.93 (4H, s), 3.33 (4H, s), 2.69(1H, m), 1.26 (2H, m), 1.08 (2H, m). (2-Chloro-5-fluoro- phenyl)-[4-(5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- Amine 577

method 5: RT: 3.48 min, MI: 472 [M + H] 1H NMR (DMSO, 500 MHz,) 9.07(1H, s), 8.28 (1H, d), 8.17 (1H, s), 8.05 (1H, s), 7.78 (2H, s), 7.41(1H, dd), 6.98 (1H, d), 3.92 (4H, s), 3.32 (4H, s), 2.68 (1H, m), 2.32(3H, s), 1.25 (2H, m), 1.08 (2H, m). (2-Chloro-5- methyl-phenyl)-[4-(5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- Amine 578

method 5: RT: 5.25 min, MI: 476 [M + H] 1H NMR (DMSO, 500 MHz,) 9.07(1H, s), 8.33 (1H, d), 8.19 (1H, s), 8.14 (1H, s), 7.97 (1H, d), 7.82(1H, dd), 7.37-7.32 (1H, m), 7.10-7.06 (1H, m), 3.93 (4H, s), 3.33 (4H,s). 2.69 (1H, m), 1.26 (2H, m), 1.09 (2H, m). (2-Chloro-3-fluoro-phenyl)-[4-(5- cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- Amine 579

44 5-Cyclopropyl-2- (6,7-dimethoxy- quinolin-4-yl)-4- piperazin-1-yl-pyrido[3,4- d]pyrimidine 580

471.9 (CDCl₃) 9.12 (s, 1H), 8.41 (dd, J = 5.3; 0.4 Hz, 1H), 8.05 (s,1H), 7.98 (dd, J = 7.0; 3.1 Hz, 1H), 7.95 (s, 1H), 7.85 (dd, J = 5.3;1.3 Hz, 1H), 7.02 (dd, J = 10.8; 8.9 Hz, 1H), 6.89 (m, 1H), 6.45 (m,1H), 3.82 (s, 3H), 3.78 (br s, 4H), 3.03 (m ,4H), 2.70 (m, 1H), 1.87 (brs, exch. H's), 1.27 (m, 2H), 1.01 (m, 2H) [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(2-fluoro-5-methoxy- phenyl)-amine 581

390.10 (M + H) N-[4-(5- Cycopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- acetamide 582

348.05 (M + H) 4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-ylamine 583

418.15 (M + H) N-[4-(5- Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- isobutyramide 584

416.10 (M + H) Cyclopropane- carboxylic acid [4- (5-cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]- amide 585

438 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(3,3- difluorocyclo- butyl)-amine 586

452.0 (M + H) (dmso-d6) 9.14 (br s, exch. H's), 9.07 (s, 1H), 8.22 (s,1H), 8.09 (d, J = 6.4 Hz, 1H), 8.02 (br s, 1H), 7.70 (d, J = 6.3 Hz,1H), 7.47 (m, 2H), 7.40 (m, 2H), 7.30 (m, 1H), 5.10 (m, 1H), 3.90 (br s,4H), 3.33 (br s, 4H), 2.66 (m, 1H), 1.58 (d, J = 6.7 Hz, 3H), 1.26 (m,2H), 1.08 (m, 2H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-((R)- 1-phenyl-ethyl)- amine 587

452.0 (M + H) (dmso-d6) 9.12 (br s, exch. H's), 9.06 (s, 1H), 8.21 (s,1H), 8.09 (d, J = 6.4 Hz, 1H), 7.98 (br s, 1H), 7.680 (d, J = 6.3 Hz,1H), 7.47 (m, 2H), 7.39 (m, 2H), 7.29 (m, 1H), 5.10 (m, 1H), 3.89 (br s,4H), 3.33 (br s, 4H), 2.65 (m, 1H), 1.57 (d, J = 6.7 Hz, 3H), 1.26 (m,2H), 1.08 (m, 2H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-((S)- 1-phenyl-ethyl)- amine 588

455.0 (M + H) (CDCl3) 9.05 (s, 1H), 8.95 (s, 1H), 8.40 (dd, J = 5.2; 0.3Hz, 1H), 8.05 (s, 1H), 7.89 (dd, J = 5.2; 1.4 Hz, 1H), 7.76 (s, 1H),7.51 (m, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.33 (d, J = 7.8 Hz, 1H), 4.10(s, 3H), 375 (br s, 4H), 3.03 (m, 4H), 2.71 (m, 1H), 1.96 (br s, exch.H's), 1.27 (m, 2H), 1.01 (m, 2H) [4-(5-Cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(6- methoxy-pyridin-2-yl)-amine 589

472.0 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- fluoro-3-methoxy- phenyl)-amine 590

489.9 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,6- difluoro-4- methoxy-phenyl)-amine 591

468.0 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3- methoxy-2-methyl- phenyl)- amine592

method 5: RT: 2.59 min, MI: 488 [M + H] 1H NMR (DMSO, 500 MHz,) 9.06(1H, s), 8.32 (1H, d), 8.19 (1H, s), 8.12 (1H, s), 7.80 (1H, dd), 7.76(1H, d), 7.41 (1H, d), 6.72 (1H, dd), 3.92 (4H, s), 3.77 (3H, s), 3.33(4H, s), 2.68 (1H, m), 1.26 (2H, m), 1.08 (2H, m). (2-Chloro-5-methoxy-phenyl)- [4-(5-cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- amine 594

method 5: RT: 2.19 min, MI: 442 [M + H] 1H NMR (DMSO, 500 MHz), 9.55(1H, s), 9.06 (1H, s), 8.31 (1H, d), 8.19 (1H, s), 7.93 (1H, s),7.76-7.72 (3H, m), 7.16 (2H, t), 3.92 (4H, s), 3.33 (4H, s), 2.69 (1H,m), 1.25 (2H, m), 1.09 (2H, m). [4-(5-Cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(4- fluoro-phenyl)- amine595

method 5: RT: 3.33 min, MI: 492 [M + H] 1H NMR (DMSO, 500 MHz,) 9.86(1H, s), 9.07 (1H, s), 8.43 (1H, d), 8.19 (1H, s), 8.02 (1H, s), 7.99(2H, d), 7.83 (1H, dd), 7.64 (2H, d), 3.94 (4H, s), 3.34 (4H, s), 2.69(1H, m), 1.27 (2H, m), 1.08 (2H, m). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(4-trifluoromethyl- phenyl)-amine 596

method 5: RT: 2.9 min, MI: 483 [M + H] 1H NMR (DMSO, 500 MHz,) 9.07 (2H,s), 8.71 (1H, d), 8.40 (1H, d), 8.24 (1H, s), 8.19 (1H, s), 7.88 (1H,dd), 7.72 (1H, d), 7.48 (1H, dd), 3.92 (4H, s), 3.34 (4H, s), 2.69 (1H,m), 1.25 (2H, m), 1.08 (2H, m). [4-(5-Cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(4- trifluoromethyl-phenyl)-amine 597

method 5: RT: 3.41 min, MI: 526 [M + H] 1H NMR (DMSO, 500 MHz,) 9.07(1H, s), 9.02 (1H, s), 8.69 (1H, d), 8.39 (1H, d), 8.25 (1H, s), 8.19(1H, s), 7.86 (1H, dd), 7.73 (1H, d), 7.36 (1H, dd), 3.94 (4H, s), 3.34(4H, s), 2.69 (1H, m), 1.26 (2H, m), 1.08 (2H, m). (2-Chloro-5-trifluoromethyl- phenyl)- [4-(5-cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]- amine 598

method 5: RT: 5.48 min, MI: [M + H] 1H NMR (500 MHz, DMSO) 8.93 (1H, s),8.13 (1H, d), 8.06 (1H, s), 7.74 (1H, s), 7.51 (1H, d), 6.87 (1H, s),3.77 (4H, m, br), 2.83 (4H, m, br), 2.62-2.61 (1H, m), 1.66 (6H, s),1.25-1.23 (2H, m), 1.02-1.01 (2H, m). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(2,2,2-trifluoro-1,1- dimethyl-ethyl)- amine 599

method 5: RT: 2.85 min, MI: 460 [M + H] 1H NMR (DMSO, 500 MHz,) 9.70(1H, s), 9.06 (1H, s), 8.37 (1H, d), 8.18 (1H, s), 8.12-8.07 (1H, m),7.94 (1H, s), 7.77 (1H, d), 7.37 (2H, m), 3.94 (4H, s), 3.34 (4H, s),2.69 (1H, m), 1.27 (2H, m), 1.08 (2H, m). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(3,4-difluoro-phenyl)- amine 600

428 (dmso-d6) 9.39 (s, 1H), 8.97 (s, 1H), 8.37 (s, 1H), 8.25 (d, J = 5.3Hz, 1H), 8.09 (s, 1H), 7.63 (dd, J = 5.2; 1.4 Hz, 1H), 7.53 (d, J = 2.2Hz, 1H), 6.34 (d, J = 2.2 Hz, 1H), 3.77 (s, 3H), 3.70 (br s, 4H), 3.30-3.32 (exch. H's), 2.85 (br s, 4H), 2.63 (m, 1H), 1.25 (m, 2H), 1.02 (m,2H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(1- methyl-1H- pyrazol-3-yl)- amine 601

method 5: RT: 2.29 min, MI: 448.35 [M + H] 1H NMR (500 MHZ, DMSO) 9.16(2H, s, br), 9.06 (1H, s), 8.21 (1H, s), 8.08 (1H, d), 8.05 (1H, s),4.85 (1H, d), 3.96 (4H, m, br), 3.80 (1H, s, br), 3.37-3.32 (4H, m),2.66-2.62 (1H, m), 2.02-1.98 (2H, m), 1.87- 1.85 (2H, m), 1.73 (1H, t),1.65-1.61 (3H, m), 1.27-1.23 (2H, m), 1.09- 1.06 (2H, m).[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(4- fluorocyclohexyl)- amine 602

553.1 (M + H) (CDCl₃) 9.07 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 8.08 (brs, 1H), 8.02 (s, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.24 (dd, J = 8.4 Hz,1H), 7.06 (br s, 1H), 6.98 (br s, 1H), 6.82 (br d, J = 7.08 Hz, 1H),6.69 (dd, J = 8.4; 1.9 Hz, 1H), 3.95 (m, 5H), 3.55 (m, br s, 1H), 3.25(br s, 5H), 2.60 (m, 5H), 2.34 (s, 3H), 1.91 (m, 1H), 1.7 br s (exch.H's), 1.24 (m, 2H), 0.97 (+/−)-(cis)-1-(5- Cylcopropyl-2-(2-[3-(4-methyl- piperazin-1-yl)- phenylamino]- pyridin-4-yl}- pyrido[3,4-d]pyrimidin-4-yl)- piperidine-3,4-diol (m, 2H) 603

500.0 (MH)+ (4-Cyclopropyl- 2,6-difluoro- phenyl)-[4-(5- cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]- amine 604

473.9 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,6- difluoro-4-methyl- phenyl)-amine605

428.0 (M + H) (CDCl₃) 9.13 (s, 1H), 8.37 (d, J = 5.4 Hz, 1H), 8.05 (s,1H), 7.81 (s, 1H), 7.73 (dd, J = 5.4; 1.3 Hz, 1H), 7.47 (br s, 1H), 7.37(d, J = 1.5 Hz, 1H), 7.26 (s, 1H, *“shoulder” under solvent's peak),3.77 (br s, 4H), 3.71 (s, 3H), 3.03 (m, 4H), 2.70 (m, 1H), 2.93 (br s,exch. H's), 1.26 (m, 2H), 1.01 (m, 2H) [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(1-methyl-1H- imidazol-4-yl)- amine 606

468.0 (M + H) (CDCl₃) 9.11 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.04 (s,1H), 8.01 (s, 1H), 7.78 (dd, J = 5.2; 1.3 Hz, 1H), 7.45 (m, 2H), 7.35(m, 2H), 7.17 (br s, 1H), 7.06 (m, 1H), 3.79 (br s, 4H), 3.68 (m, 2H),3.14 (br s, exch. H's), 2.63 (m, 5H), 2.60 (m, 2H), 1.26 (m, 2H), 1.0(m, 2H) 2-{4-[5- Cyclopropyl-2-(2- phenylamino- pyridin-4-yl)-pyrido[3,4- d]pyrimidin-4-yl]- piperazin-1-yl}- ethanol 607

498.0 (M + H) (CDCl₃) 9.11 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.04 (s,1H), 8.00 (s, 1H), 7.78 (dd, J = 5.3; 1.3 Hz, 1H), 7.45 (m, 2H), 7.35(m, 2H), 7.06 (m, 1H), 6.98 (br s, 1H), 3.87 (m, 1H), 3.79 (m, 5H), 3.54(d, J = 11.5; 4.4 Hz, 1H), 3.40-2.10 (br signal, —OH's), 2.78 (m, 2H),2.64 (m, 2H), 2.58 (m, 2H), 2.40 (dd, J = 12.5 Hz,; 3.7 Hz, 1H), 1.25(m, 2H), 1.00 (m, 2H) (S)-3-{4-[5- Cyclopropyl-2-(2- phenylamino-pyridin-4-yl)- pyrido[3,4- d]pyrimidin-4-yl]- piperazin-1-yl}-propane-1,2-diol 608

498.0 (M + H) (CDCl₃) 9.11 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.04 (s,1H), 8.00 (s, 1H), 7.78 (dd, J = 5.3; 1.3 Hz, 1H), 7.45 (m, 2H), 7.35(m, 2H), 7.09 (br s, 1H), 7.06 (m, 1H), 3.87 (m, 1H), 3.79 (m, 5H), 3.54(d, J = 11.5; 4.4 Hz, 1H), 3.40-2.10 (br signal, —OH's), 2.78 (m, 2H),2.64 (m, 2H), 2.58 (m, 2H), 2.40 (dd, J = 12.5 Hz; 3.7 Hz, 1H), 1.25 (m,2H), 1.00 (m, 2H) (R)-3-{4-[5- Cyclopropyl-2-(2- phenylamino-pyridin-4-yl)- pyrido[3,4- d]pyrimidin-4-yl]- piperazin-1-yl}-propane-1,2-diol 609

468.0 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3- methoxy-4-methyl- phenyl)-amine 610

484.0 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3,4- dimethoxy- phenyl)-amine 611

514.0 (MH)+ [4-(5-Cylcopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- (3,4,5-trimethoxy- phenyl)-amine 612

466.15 (M + H) N-[4-(5- Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-2- phenyl-acetamide 613

458.15 (M + H) N-[4-(5- Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-3,3,3- trifluoro- propionamide 614

555.25 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[4-(1- methyl-4-oxo-4λ⁵- [1,4]azaphos-phinan-4-yl)- phenyl]-amine 615

— 449.10 (M + H) 2-(2-Chloro- pyridin-4-yl)-5- cyclopropyl-4-[3-(2,2,2-trifluoro- ethyl)-piperazin-1- yl]-pyrido[3,4- d]pyrimidine 616

method 5: RT: 3.25 min, MI: 476 [M + H] 1H NMR (DMSO, 500 MHz) 9.05 (2H,bs), 8.93 (1H, bs), 8.21 (1H, d), 8.17 (1H, s), 7.88 (1H, s), 7.73 (1H,dd), 7.48 (1H, m), 7.25 (1H, m), 4.68 (4H, bs), 3.89 (4H, bs), 2.70 (1H,m), 1.28-1.25 (2H, m), 1.06-1.05 (2H, m). (2-Chloro-6-fluoro-phenyl)-[4-(5- cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- amine 617

method 5: RT: 3.36 min, MI: 490 [M + H] 1H NMR (DMSO, 500 MHz) 9.04 (1H,s), 8.80 (1H, bs), 8.17 (1H, s), 8.15 (1H, d), 7.80 (1H, s), 7.67 (1H,d), 7.30 (1H, dd), 7.19 (1H, m), 3.91 (4H, bs), 3.31 (4H, bs), 2.68 (1H,m), 2.24 (3H, s), 1.23 (2H, m), 1.08-1.07 (2H, m). (6-Chloro-2-fluoro-3-methyl-phenyl)- [4-(5-cylcopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- amine 618

method 5: RT: 2.62 min, MI: 494 [M + H] 1H NMR (DMSO, 500 MHz) 9.05 (1H,s), 8.86 (1H, bs), 8.20 (1H, d), 8.17 (1H, s), 7.88 (1H, s), 7.73 (1H,dd), 7.47 (1H, m), 7.25 (1H, m), 3.89 (4H, bs), 3.31 (4H, bs), 2.68 (1H,m), 1.28-1.25 (2H, m), 1.08-1.07 (2H, m). (3-Chloro-2,6-difluoro-phenyl)- [4-(5-cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- amine 619

method 5: RT: 3.04 min, MI: 438 [M + H] NMR:- (1H, d6-dmso, 500 MHz)9.30 (1H, s), 9.04 (1H, s), 8.69 (1H, s), 8.29 (1H, d), 7.90 (1H, s),7.74 (2H, d), 7.65 (1H, dd), 7.27 (2H,tr), 6.89 (1H, tr), 4.26-4.20 (1H,m), 3.67 (2H, br s), 3.46 (2H, br s), 2.93 (2H, br s), 2.83 (2H, br s),2.46-2.43 (2H, m partially hidden by large DMSO peak), 2.21-2.14 (2H,m), [4-(5-Cyclobutyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- phenyl-amine 2.10-2.03 (1H, m), 1.92-1.86 (1H, m). 620

method 5: RT: 3.39 min, MI: 474 [M + H] NMR: (1H, d6-dmso, 500 MHz) 9.02(1H, s), 8.75 (1H, s), 8.68 (1H, s), 8.14 (1H, d), 7.77 (1H, s), 7.63(1H, dd), 7.29-7.23 (1H, m), 7.15 (2H, t), 4.22 (1H, dq), 3.63 (2H, brs), 3.50 (2H, br s), 2.90 (2H, br s), 2.78 (2H, br s), 2.44-2.42 (2H, m,partially obscured by DMSO peak), 2.20-2.12 (2H, m), 2.10-[4-(5-Cyclobutyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-2,6- difluoro-phenyl)- amine 2.01 (1H, m), 1.91-1.86 (1H,m) 621

method 5: RT: 2.24 min, MI: 452.37 [M + H] 1H NMR (500 MHz, DMSO) 8.93(1H, s), 8.13 (1H, d), 8.06 (1H, s), 7.53 (1H, s), 7.44 (1H, dd), 7.04(1H, d), 4.42-4.38 (1H, m), 3.75- 3.57 (4H, m, br), 2.84 (4H, m),2.62-2.58 (2H, m), 2.27-1.97 (4H, m), 1.77-1.69 (1H, m),, 1.26-1.22 (2H,m), 1.01-1.00 (2H, m). [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3,3- difluoro- cyclopentyl)-amine 622

466.30 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3- isopropyl-phenyl)- amine 623

452.25 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3- ethyl-phenyl)- amine 624

— 435.10 (M + H) 2-(2-Chloro- pyridin-4-yl)-5- cyclopropyl-4-(3-trifluoromethyl- piperazin-1-yl)- pyrido[3,4- d]pyrimidine 625

599.20 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[4-(1- ethyl-4-oxo-4λ⁵- [1,4]azaphos-phinan-4-yl)-2- methoxy-phenyl]- amine 626

472.00 (M + H) N-(4-{5- Cyclopropyl-4-[3- (2,2,2-trifluoro-ethyl)-piperazin-1- yl]-pyrido[3,4- d]pyrimidin-2-yl}- pyridin-2-yl)-acetamide 627

method 5: RT: 0.48 min, MI: 472 [M + H] 1H NMR (DMSO, 500 MHz,) 9.62(1H, s), 9.06 (1H, s), 8.32 (1H, d), 8.19 (1H, s), 7.96 (1H, s), 7.74(1H, d), 7.62 (1H, dd), 7.28 (1H, m), 7.17-7.13 (1H, m), 3.85 (7H, m),3.34 (4H, s), 2.68 (1H, m), 1.27 (2H, m), 1.09 (2H, m).[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(4- fluoro-3-methoxy- phenyl)-amine 628

method 5: RT: 2.37 min, MI: 490 [M + H] 1H NMR (DMSO, 500 MHz, 1IGO570)9.27 (1H, s), 9.06 (1H, s), 8.30 (1H, d), 8.18 (1H, s), 8.06 (1H, s),7.96 (1H, t), 7.78 (1H, dd), 7.39 (1H, t), 3.96 (4H, s), 3.84 (3H, s),3.33 (4H, s), 2.68 (1H, m), 1.27 (2H, m), 1.08 (2H, m).[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4- difluoro-5- methoxy-phenyl)- amine 629

method 5: RT: 2.16 min, MI: 402.22 [M + H] 1H NMR (500 MHz, CDCl3) 9.07(1H, s), 8.21 (1H, s), 8.04 (2H, d), 7.65 (1H, d), 4.10-3.74 (8H, m,br), 3.26 (2H, d), 2.66-2.62 (1H, m), 1.28-1.24 (2H, m), 1.15-1.13 (1H,m), 1.09-1.07 (2H, m), 0.57-0.56 (2H, m), 0.32-0.31 (2H, m).Cyclopropylmethyl- [4-(5-cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- amine 630

method 5: RT: 1.61 min, MI: 362.19 [M + H] 1H NMR (500 MHz, DMSO) 8.94(1H, s), 8.12 ('1H, d), 8.06 (1H, s), 7.48 (1H, s), 7.41 (1H, dd), 6.72(1H, d), 3.77-3.55 (4H, m), 2.85 (4H, m, br), 2.82 (3H, d), 2.63-2.59(1H, m), 1.25-1.22 (2H, m), 1.02- 1.00 (2H, m). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-methyl-amine 631

method 5: RT: 3.04 min, MI: 467 [M + H] 1H NMR (DMSO, 500 MHz,) 10.30(1H, s), 9.06 (1H, s), 8.50 (1H, d), 8.23 (1H, dd), 8.19 (1H, s), 8.05(1H, s), 7.92 (1H ,dd), 7.75 (1H, t), 7.52 (1H, dd), 3.94 (4H, s), 3.33(4H, s), 2.68 (1H, m), 1.26 (2H, m), 1.09 (2H, m). 4-[4-(5-Cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-ylamino]-2-fluoro- benzonitrile 632

method 5: RT: 1.96 min, MI: 438 [M + H] 1H NMR (DMSO, 400 MHz, 90° C.,1IGO565_2) 8.99 (1H, s), 8.31 (1H, dd), 8.18 (1H, s), 7.95 (1H, s), 7.72(1H, dd), 7.70-7.67 (2H, dd), 7.32 (2H, t), 6.97 (1H, t), 4.22 (2H, t),4.05 (2H, t), 3.50 (2H, t), 3.20 (2H, t), 2.44 (1H, m), 2.11 (2H, quin),1.27-1.23 (2H, m), 0.97-0.93 (2H, m). [4-(5-Cyclopropyl-4-[1,4]diazepan-1- yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-phenyl-amine 633

method 5: RT: 2.02 min, MI: 446.23 [M + H] 1H NMR (500 MHz, DMSO) 8.92(1H, s), 8.08 (1H, d), 8.06 (1H, s), 7.49 (1H, s), 7.35 (1H, dd), 6.61(1H, d), 4.53 (1H, d), 3.83-3.67 (5H, m, br), 3.51-3.42 (1H, m), 2.85(4H, m), 2.61-2.60 (1H, m), 2.53 (2H, m), 1.97-1.95 (2H, m), 1.85-1.83(2H, m), 1.24-1.20 (6H, m), 1.01- 0.95 (6H, m). 4-[4-(5- Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2- ylamino]-cyclohexanol 634

method 5: RT: 2.29 min, MI: 506 [M + H] 1H NMR (DMSO, 500 MHz) 9.06 (1H,s), 8.83 (1H, bs), 8.17 (1H, s), 8.16 (1H, d), 7.81 (1H, s), 7.67 (1H,dd), 7.25 (1H, t), 7.03 (1H, dd), 4.7 (4H, bs), 3.87 (3H, s), 3.31 (4H,m) 2.68 (1H, m), 1.26-1.23 (2H, m), 1.06-1.05 (2H, m).(2-Choro-6-fluoro- 3-methoxy- phenyl)-[4-(5- cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]- amine 635

method 5: RT: 2.53 min, MI: 494 [M + H] 1H NMR (DMSO, 500 MHz) 9.05 (1H,s), 9.01 (1H, s), 8.86 (1H, bs), 8.18 (1H, s), 8.17 (1H, d), 7.87 (1H,s), 7.71 (1H, dd), 7.35 (1H, m), 3.89 (4H, bs), 3.31 (4H, m) 2.68 (1H,m), 2.35 (3H, s), 1.25-1.23 (2H, m), 1.08-1.06 (2H, m). (2-Chloro-3,6-difluoro-phenyl)- [4-(5-cyclopropyl- 4-piperaizn-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- amine 636

method 5: RT: 1.36 min, MI: 432 [M + H] 1H NMR (DMSO, 500 MHz) 9.05 (1H,s), 9.01 (1H, s), 8.86 (1H, bs), 8.18 (1H, s), 8.17 (1H, d), 7.87 (1H,s), 7.71 (1H, dd), 7.35 (1H, m), 3.89 (4H, bs), 3.31 (4H, m) 2.68 (1H,m), 2.35 (3H, s), 1.25-1.23 (2H, m), 1.08-1.06 (2H, m).{4-[5-Cyclopropyl- 4-(2,2,3,3,5,5,6,6- octadeuterio- piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}- phenyl-amine 637

494.0 (MH)+ (4-Cyclopropyl-3- methoxy-phenyl)- [4-(5-cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]- amine638

467.0 (M + H) (dmso-d6) 9.61 (br s, 1H), 8.95 (s, 1H), 8.21 (d, J = 5.6Hz, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.67 (dd, J = 5.6; 1.1 Hz, 1H),7.63 (d, J = 7.8 Hz, 2H), 7.29 (dd, J = 7.8; 8.0 Hz, 2H), 6.96 (t, J =7.2 Hz, 1H), 6.06 (br s, 2H), 3.47-3.95 (br m, 4H), 3.47-3.37 (m, 5H),2.55 (m, 1H), 1.21 (m, 2H), 0.99 (m, 2H) 4-[5-Cyclopropyl-2-(2-phenylamino- pyridin-4-yl)- pyrido[3,4- d]pyrimidin-4-yl]-piperazine-1- carboxylic acidamide 639

502 (M + H) N-[4-(5- Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-2- (2,6-difluoro- phenyl)-acetamide 640

484.20 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- fluoro-5-propyl- phenyl)-amine 641

482.15 (4-Cyclopropyl-2- fluoro-phenyl)-[4- (5-cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]- amine 642

542.10 (M + H) (4-{5-Cyclopropyl- 4-[3-(2,2,2- trifluoro-ethyl)-piperazin-1-yl]- pyrido[3,4- d]pyrimidin-2-yl}- pyridin-2-yl)-(2,6-difluoro-phenyl)- amine 643

506.20 (M + H) (4-{5-Cyclopropyl- 4-[3-(2,2,2- trifluoro-ethyl)-piperazin-1-yl]- pyrido[3,4- d]pyrimidin-2-yl}- pyridin-2-yl)-penyl-amine 644

470 (M + H) 1H NMR (500 MHz, DMSO) 8.92 (1H, s), 8.05 (1H, s), 8.04 (1H,d), 7.55 (1H, s), 7.40 (1H, dd), 7.35- 7.29 (2H, m), 7.24 (1H, d), 7.21(1H, d), 6.99 (1H, td), 5.08 (1H, t), 4.09-4.08 (1H, m), 3.78-3.51 (4H,m, br), 2.62-2.58 (1H, m), 1.44 (3H, d), 1.24-1.22 (2H, m), 1.01-1.00(2H, m). [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[(R)- 1-(3-fluoro- phenyl)-ethyl]-amine 645

method 5: RT: 3.83 min, MI: 449 [M + H] 1H NMR (DMSO, 500 MHz,) 9.98(1H, s), 9.05 (1H, s), 8.44 (1H, d), 8.18 (1H, s), 8.02 (1H, s), 7.97(2H, d), 7.85 (1H, dd), 7.72 (2H, d), 3.92 (4H, s), 3.33 (4H, s), 2.68(1H, m), 1.25 (2H, m), 1.07 (2H, m). 4-[4-(5- Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2- yalmino]-benzonitrile 646

method 5: RT: 4.3 min, MI: 492 [M + H] 1H NMR (DMSO, 500 MHz,) 9.79 (1H,s), 9.06 (1H, s), 8.42 (1H, d), 8.34 (1H, s), 8.18 (1H, s), 7.99 (1H,s), 7.94 (1H, d), 7.80 (1H, dd), 7.52 (1H, t), 7.24 (1H, d), 3.92 (4H,s), 3.34 (4H, s), 2.69 (1H, m), 1.27 (2H, m), 1.09 (2H, m).[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(3- trifluoromethyl- phenyl)-amine 649

method 5: RT: 2.44 min, MI: 490 [M + H] 1H NMR (DMSO, 500 MHz) 9.04 (1H,s), 8.79 (1H, bs), 8.17 (1H, s), 8.15 (1H, d), 7.80 (1H, s), 7.66 (1H,dd), 7.27 (1H, dd), 7.20 (1H, t), 3.88 (4H, bs), 3.31 (4H, m) 2.68 (1H,m), 2.35 (3H, s), 1.26-1.23 (2H, m), 1.08-1.06 (2H, m). (3-Chloro-2,6-difluoro-phenyl)- [4-(5-cylcopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- amine 650

method 5: RT: 3.26 min, MI: 478 [M + H] 1H NMR (DMSO, 500 MHz,) 9.06(1H, s), 8.85 (1H, s), 8.18 (2H, s), 7.84 (1H, s), 7.71 (1H, dd), 7.29(2H, t), 3.90 (4H, s), 3.33 (4H, s), 2.69 (1H, m), 1.25 (2H, m), 1.08(2H, m). [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- (2,4,6-trifluoro- phenyl)-amine 651

method 5: RT: 3.22 min, MI: 460 [M + H] 1H NMR (DMSO, 500 MHz, 1IGO581)9.13 (1H, s), 9.06 (1H, s), 8.28 (1H, d), 8.18 (1H, s), 8.12-8.07 (1H,m), 8.02 (1H, s), 7.75 (1H, dd), 7.35-7.30 (1H, m), 7.11-7.06 (1H, m),3.92 (4H, s), 3.33 (4H, s), 2.69 (1H, m), 1.26 (2H, m), 1.08 (2H, m).[4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4- difluoro-phenyl)- amine 652

method 5: RT: 2.71 min, MI: 470.37 [M + H] 1H NMR (500 MHz, DMSO) 8.92(1H, s), 8.05 (1H, s), 8.03 (1H, d), 7.63 (1H, s), 7.42 (2H, dd), 7.39(1H, dd), 7.26 (1H, d), 7.15 (1H, t), 7.10 (2H, t), 5.06 (1H, 03.77-3.52(4H, m), 2.83 (4H, m), 2.62-2.58 (1H, m), 1.43 (3H, s), 1.30 (1H, d),1.24-1.22 (2H, m), 1.01-1.00 (2H, m). 4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-[(R)-1(4-fluoro- phenyl)-ethyl]- amine 653

method 5: RT: 5.46 min, MI: 488.35 [M + H] 1H NMR (500 MHz, DMSO) 8.92(1H, s), 8.06 (1H, s), 8.04 (1H, d), 7.61 (1H, d), 7.39 (1H, dd), 7.27(1H, dt), 7.24 (1H, d), 7.00 (2H, t), 5.47 (1H, t), 3.78-3.54 (4H, m),2.86 (4H, m), 2.63-2.62 (2H, m), 2.37- 2.35 (1H, m), 1.55 (3H, d), 1.24-1.22 (2H, m), 1.01-1.00 (2H, m). [4-(5-Cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-[(R)- 1-(2,6-difluoro-phenyl)-ethyl]- amine 654

method 5: RT: 2.31 min, MI: 442.34 [M + H] 1H NMR (500 MHz, DMSO) 9.28(1H, s), 8.93 (1H, s), 8.24 (1H, d), 8.11 (1H, s), 7.66 (1H, d), 7.62(2H, d), 7.26 (2H, t), 6.89 (1H, t), 3.68 (4H, s, br), 3.15 (1H, d),2.82 (4H, s, br), 2.59-2.57 (1H, m), 1.26-1.24 (2H, m), 1.03-1.02 (2H,m). [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-5-fluoro-pyridin-2- yl]-phenyl-amine 655

544 (M + H) 1-{5-Cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-4- carboxylicacid isopropylamide 656

502 (M + H) 1-{5-Cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-4- carboxylicacid amide 657

516 (M + H) N-(1-{5- Cyclopropyl-2-[2- (2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidin-4-yl)- acetamide658

548 (M + H) 1-{5-Cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-4- carboxylicacid (2- fluoro-ethyl)-amide 659

458 N-{4-[5- Cyclopropyl-4- ((S)-3- trifluoromethyl- piperazin-1-yl)-pyrido[3,4- d]pyrimidine-2-yl]- pyridin-2-yl}- acetamide 660

— 435 2-(2-Chloro- pyridin-4-yl)-5- cyclopropyl-4- ((R)-3-trifluoromethyl- piperazin-1-yl)- pyrido[3,4- d]pyrimidine 661

482 (4-{5-Cyclopropyl- 4-[4-(2-methoxy- ethyl)-piperazin-1-yl]-pyrido[3,4- d]pyrimidin-2-yl}- pyridin-2-yl)- phenyl-amine 662

500 (4-{5-Cyclopropyl- 4-[4-(2-methoxy- ethyl)-piperazin-1-yl]-pyrido[3,4- d]pyrimidin-2-yl}- pyridin-2-yl)-(4- fluoro-phenyl-amine 663

530 (4-{5-Cyclopropyl- 4-{4-(2- methanesulfonyl- ethyl)-piperazin-1-yl]-pyrido[3,- d]pyrimidin-2-yl}- pyridin-2-yl)- phenyl-amine 664

548 (4-{5-Cyclopropyl- 4-[4-(2- methanesulfonyl- ethyl)-piperazin-1-yl]-pyrido[3,4- d]pyrimidin-2-yl}- pyridin-2-yl)-(4- fluoro-phenyl)-amine 665

522 Cyclopropane- carboxylic acid (4- {5-cyclopropyl-4- [4-(2-methanesulfonyl- ethyl)-piperazin-1- yl]-pyrido[3,4- d]pyrimidin-2-yl}-pyridin-2-yl)- amide 666

474 Cyclopropane- carboxylic acid (4- {5-cyclopropyl-4- [4-(2-methoxy-ethyl)-piperazin-1- yl]-pyrido[3,4- d]pyrimidin-2-yl}- pyridin-2-yl)-amide 667

482 (5-Cyclopropyl-2- fluoro-phenyl)-[4- (5-cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]- amine 668

599 (M + H) 1-{5-Cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-4- carboxylicacid (2- pyrrolidin-1-yl- ethyl)-amide 669

516 (M + H) 1-{5-Cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-4- carboxylicacid methylamide 670

461.2 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,4- difluoro-pyridin-3- yl)-amine 671

461.0 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,6- difluoro-pyridin-3- yl)-amine 672

443.1 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(6- fluoro-pyridin-3- yl)-amine 673

method 5: RT: 2.41 min, MI: 466.32 [M + H] 1H NMR (500 MHz, DMSO) 9.05(1H, s), 8.19 (1H, s), 8.10 (1H, d), 7.91 (1H, s, br), 7.64 (1H, d, br),3.98-3.80 (5H, m), 3.31 (4H, m, br), 2.67-2.62 (1H, m), 2.03-2.01 (2H,m), 1.94-1.79 (3H, m), 1.54-1.51 (1H, m), 1.35-1.32 (1H, m), 1.26- 1.24(2H, m), 1.07-1.06 (2H, m). [4-(5-Cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(3,3- difluoro-cyclohexyl)-amine 674

514 (M + H) 1-[2-(2- Cyclohexylamino- pyridin-4-yl)-5- cyclopropyl-pyrido[3,4- d]pyrimidin-4-yl]- piperidine-4- carboxylic acidisopropylamide 675

455.1 (dmso-d6) 9.84 (br s, 1H), 8.98 (s, 1H), 8.26 (d, J = 5.7 Hz, 1H),8.12 (s, 1H), 7.99 (s, 1H), 7.74 (dd, J = 5.7; 1.2 Hz, 1H), 7.67 (d, J =7.8 Hz, 2H), 7.38 (app t, J = 8.00 Hz, 2H), 7.07 (app t, 6.8 Hz, 1H),4.19 (large br s, exch. H's), 3.77 (br s, 4H), 3.70-3.47 (m, 2H),3.47-3.25 (+/−)-(cis)-1-[5- Cyclopropyl-2-(2- phenylamino- pyridin-4-yl-pyrido[3,4- d]pyrimidin-4-yl]- piperidine-3,4-diol (m, 1H), 3.13-1.78(m, 1H), 1.68 (br s, 1H), 1.47-1.13 (m, 2H), 1.13-0.87 (m, 2H)

The following compounds were synthesised according to the generalsynthesis shown in scheme [B4]

Analysis Ex Amine 1 Amine 2 LCMS NMR Name 676

455.1 (M + H) NMR (dmso-d6) 9.74 (br s, 1H), 8.98 (s, 1H), 8.27 (d, J =5.6 Hz, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.73 (d, J = 6.4 Hz, 1H), 7.68(d, J = 8.0 Hz, 2H), 7.36 (app t, J = 8.0 Hz, 2H), 7.04 (app t, J = 7.2Hz, (+/−)-(trans)-1-[5- Cyclopropyl-2-(2- phenylamino- pyridin-4-yl)-pyrido[3,4- d]pyrimidin-4-yl]- piperidine-3,4-diol 1H), 3.80 (large brs, exch. H's - overlapping other signals), 3.52 (br s, 2H), 3.40-3.35(m, 2H), 2.23-1.83 (m, 2H), 1.55 (br s, 1H), 1.49 (br s, 1H), 1.35 (brs, 1H), 1.12-0.92 (m, 2H) 677

481.1 (M + H) (CDCl₃) 10.39 (br s, 1H), 8.97 (br s, 1H), 8.65 (s, 1H),8.50 (d, J = 4.8 Hz, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.35 (s, 1H), 8.10(s, 1H), 7.89 (d, J = 4.9 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 5.25-4.65(+/−)-2-{4-[5- Cyclopropyl-4- ((trans)-3,4- dihydroxy- piperidin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-ylamino}- (m, 2H), 4.40-3.70(m, isonicotinonitrile 4H), 3.52 (br s, 1H), 2.25-1.85 (m, 1H), 1.65-1.50 (m, 1H), 1.50-1.15 (m, 3H), 1.10-0.90 (m, 2H) 678

553.26 (M + H) (CDCl₃) 9.16 (s, 1H), 8.94 (s, 1H), 8.30 (d, J = 5.3 Hz,1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.66 (dd, J = 5.2; 1.0 Hz, 1H), 7.34(app t, J = 2.0 Hz, 1H), 7.22 (dd, J = 8.0; 1.1 Hz, 1H), 7.11 (app t, J= 8.1 Hz, 1H), 6.52 (dd, J = 8.2; 1.8 Hz, 1H), (+/−)-(trans)-1-(5-Cyclopropyl-2-{2- [3-(4-methyl- piperazin-1-yl)- phenylamino]-pyridin-4-yl}- pyrido[3,4d]pyrimidin- 4-yl)-piperidine- 3,4-diol5.28-4.67 (m, 2H), 4.28- 3.71 (m, 2H), 3.50 (br s, 1H), 3.15-3.11 (m,4H), 2.61-2.53 (m, 1H), 2.49- 2.45 (m, 4H), 2.23 (s, 3H), 2.18-1.73 (m,2H), 1.44-1.11 (m, 3H), 1.10- 0.90 (m, 2H) 679

500 (M + H) 1-[2-(2- Cyclopentylamino- pyridin-4-yl)-5- cyclopropyl-pyrido[3,4- d]pyrimidin-4-yl]- piperidine-4- carboxylicacidisopropylamide 680

479.1 (M + H)+ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.69 (s, 1 H) 8.98 (s, 1H) 8.81 (s, 1 H) 8.40 (dd, J = 5.3, 0.8 Hz, 1 H) 8.21- 8.30 (m, 1 H)8.10 (s, 1 H) 7.92 (dd, J = 5.1, 1.4 Hz, 1 H) 3.77 (d, J = 11.3 Hz, 4 H)2.85 (br. s., 4 H) 2.59-2.65 (m, 1 H) 4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(3,5,6-trifluoro-pyridin-2- yl)-amine 1.21-1.31 (m, 3 H) 1.00- 1.07 (m, 2 H)681

522.19 (M + H) 1H NMR (400 MHz, DMSO-d6) 9.55 (1 H, s), 9.07 (1 H, s),8.73-9.00 (2 H, m), 8.38 (1 H, d, J = 5.5 Hz), 8.19 (1 H, s), 7.99 (1 H,s), 7.87 (2 H, d, J = 8.5 Hz), 7.75 (1 H, dd, J = 5.3, 1.3 Hz), 7.60-7.69 (4 H, m), 7.45 (2 H, t, J = 7.7 Hz), 7.25-7.36 [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-[3-(4-methyl-piperazin-1- yl)-phenyl]-amine (1 H, m), 3.94 (4 H, br. s.), 3.34(4 H, br. s.), 2.70 (1 H, br. s.), 1.21- 1.31 (2 H, m), 1.09 (2 H, d, J= 3.5 Hz) 682

479.1 (M + H)+ 1H NMR (400 MHz, DMSO-d6) 9.82 (1 H, s), 9.07 (1 H, s),8.69-8.99 (2 H, m), 8.43 (1 H, d, J = 5.3 Hz), 8.19 (1 H, s), 8.03 (1 H,s), 7.88 (4 H, s), 7.82 (1 H, dd, J = 5.3, 1.3 Hz), 3.94 (4 H, br. s.),3.34 (4 H, br. s.), [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,3,6- trifluoro-pyridin-4- yl)-amine2.67-2.75 (1 H, m), 1.26 (2 H, d, J = 8.5 Hz), 1.09 (2 H, d, J = 5.5 Hz)683

500 (M + H) Biphenyl-4-yl-[4-(5- cyclopropyl-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-amine 684

468 (M + H) 4-[4-(5- Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-ylamino]- benzoic acid 685

546 (M + H) 1-{5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-4- carboxylicacid (2- hydroxy-ethyl)- amide 686

530 (M + H) 1-{5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-4- carboxylicacid dimethylamide 687

565.18 (M + H) (dmso-d6) 9.99 (br s, 1H), 9.87 (s, 1H), 9.02 (s, 1H),8.26 (d, J = 5.8 Hz, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.76 (dd, J = 5.8;1.4 Hz, 1H), 7.37 (s, 1H), 7.27 (app t, J = 8.1 Hz, 1H), 7.15 (d, J =8.1 Hz, 1H), 6.75 (dd, J = 8.2; 1.6 Hz, 1H), 6.13 4-(5-Cyclopropyl-2-{2-[3-(4-methyl- piperazin-1-yl)- phenylamino]- pyridin-4-yl}-pyrido[3,4- d]pyrimidin-4-yl)- piperazine-1- carboxylic acid amide (brs, 1H), 4.56 (br s, exchangeable H's), 3.87- 3.81 (m, 4H), 3.67 (br s,2H), 3.60-3.50 (m, 7H), 3.19 (br s, 2H), 3.01 (app t, J = 12.2 Hz, 2H),2.89 (s, 3H), 2.65-2.60 (m, 1H), 1.31-1.26 (m, 2H), 1.09-1.04 (m, 2H)688

537.3 (M + H) (dmso-d6) 9.17 (s, 1H), 8.96 (s, 1H), 8.30 (d, J = 5.3 Hz,1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.66 (dd, J = 5.3; 1.4 Hz, 1H), 7.34(app t, J = 2.0 Hz, 1H), 7.22 (dd, J = 8.0; 1.2 Hz, 1H), 7.11 (app t, J= 8.0 Hz, 1H), 6.52 (dd, J = 8.2 Hz; 1.8 Hz, 1-(5-Cyclopropyl-2-{2-[3-(4-methyl- piperazin-1-yl)- phenylamino]- pyridin-4-yl}-pyrido[3,4- d]pyrimidin-4-yl)- piperidin-4-ol 1H), 4.82 (br s, 1H), 4.1-4.06 (m, 2H), 3.79 (br s, 1H), 3.51 (br s, 2H), 3.15-3.11 (m, 4H), 2.50(br s, 1H), 2.50-2.45 (m, 4H), 2.23 (s, 3H), 1.91- 1.87 (m, 2H), 1.54(br s, 2H), 1.27-1.24 (m, 2H), 1.04-1.02 (m, 2H) 689

— method 5: RT: 2.86 min, MI: 351.25 [M + H] 1H NMR (500 MHz, DMSO) 8.98(1H, s), 8.41 (1H, d), 8.26 (1H, d), 8.11 (1H, s), 7.95 (1H, d),3.79-3.61 (4H, m), 2.83 (4H, m), 2.65- 2.57 (1H, m), 1.26-1.24 (2H, m),1.03-1.01 (2H, m). 5-Cyclopropyl-2-(2- fluoro-pyridin-4-yl)-4-piperazin-1-yl- pyrido[3,4- d]pyrimidine 690

474 (M + H) {4-[4-(4-Amino- piperidin-1-yl)-5- cyclopropyl- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6- difluoro-phenyl)- amine 691

method 5: RT: 2.43 min, MI: 456 [M + H] 1H NMR (DMSO, 400 MHz, 1IG0596,90° C.) 9.06 (1H, s), 8.32 (1H, dd), 8.22 (1H, s), 8.10-8.05 (1H, td),7.98 (1H, s), 7.75 (1H, dd), 7.25-7.15 (2H, m), 7.09-7.03 (1H, m), 4.30{4-[5-Cyclopropyl- 4-((S)-3-methyl- piperazin-1-yl)- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(2- fluoro-phenyl)- amine (2H, m), 3.55(2H, m), 3.42 (1H, m), 3.36-3.23 (2H, m), 2.66 (1H, m), 1.32 (3H, d),1.26 (2H, m), 1.05 (2H, m). 692

method 5: RT: 2.42 min, MI: 474 [M + H] 1H NMR (DMSO, 500 MHz, 1IG0593)9.06 (1H, s), 8.22 (2H, m), 7.76 (1H, s), 7.71 (1H, dd), 7.32-7.25 (1H,m), 7.16 (2H, m), 2.67 (1H, m), 1.31 (3H, d), 1.26 (2H, m), 1.05 (2H,m). {4-[5-Cyclopropyl- 4-((S)-3-methyl- piperazin-1-yl)- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6- difluoro-phenyl)- amine [methylpiperazine side chain peaks not integrated). 693

method 5: RT: 2.27 min, MI: 456 [M + H] 1H NMR (DMSO, 400 MHz, 1IG0594,90° C.) 9.07 (1H, s), 8.32 (1H, dd), 8.22 (1H, s), 7.90 (1H, s), 7.70(3H, m), 7.11 (2H, m), 4.34 (2H, m), 3.55 (2H, m), 3.43 (1H, m), 3.30(2H, {4-[5-Cyclopropyl- 4-((S)-3-methyl- piperazin-1-yl)- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(4- fluoro-phenyl)- amine m), 2.67 (1H,m), 1.32 (3H, d), 1.24 (2H, m), 1.04 (2H, m). 694

method 5: RT: 2.65 min, MI: 475 [M + H] 1H NMR (DMSO, 400 MHz, 1IG0595,90° C.) 9.08 (1H, s), 8.94 (1H, m), 8.46 (1H, dd), 8.23 (1H, s), 8.00(1H, dd), 7.83-7.77 (1H, m), 6.69-6.65 (1H, m), 4.36 (2H, m), 3.58 (2H,m), {4-[5-Cyclopropyl- 4-((S)-3-methyl- piperazin-1-yl)- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(3,6- difluoro-pyridin-2- yl)-amine3.46-3.27 (3H, m), 2.67 (1H, m), 1.31 (3H, d), 1.27 (2H, m), 1.05 (2H,m). 695

442 (M + H) (+/−)- (1RS,2RS,4SR)- Bicyclo[2.2.1]hept- 2-yl-[4-(5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-amine 696

488 (M + H) 1H NMR (400 MHz, DMSO-d6) 9.07 (1 H, s), 8.93 (2 H, br. s.),8.22 (1 H, s), 8.07 (1 H, d, J = 6.3 Hz), 7.80-8.03 (1 H, m), 7.65 (1H,br. s.), 3.91-4.00 (2 H, m), 3.61- 3.65 (4 H, m), 3.27 -3.34 (4 H, m),2.62- 2.67(1 H, m), {4-[4-(4- Aminomethyl- piperidin-1-yl)-5-cyclopropyl- pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6-difluoro-phenyl)- amine 2.30 (1 H, br. s.), 1.85 (1 H, br. s.),1.41-1.64 (4 H, m), 1.12-1.38 (6 H, m), 1.01-1.12 (2 H, m) 697

438.1 (MH)+ [5-Cyclopropyl-2- (2-phenylamino- pyridin-4-yl)- pyrido[3,4-d]pyrimidin-4-yl]- (S)-1-pyrrolidin-2- ylmethyl-amine 698

474.3 (MH)+ {5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- (S)-1-pyrrolidin-2-ylmethyl-amine 699

method 5: RT: 2.19 min, MI: 456 [M + H] 1H NMR (DMSO, 500 MHz) 9.49 (1H,s), 8.96 (1H, s), 8.30 (1H, d), 8.14 (1H, s), 7.91 (1H, s), 7.76 (2H,m), 7.71 (1H, dd), 7.17 (2H, m), 4.17 (2H, m), 4.01 (2H, m), 3.49 (2H,m), 3.16 [4-(5-Cyclopropyl- 4-[1,4]diazepan-1- yl-pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(4- fluoro-phenyl)- amine (2H, m), 2.35(1H, m), 2.06 (2H, m), 1.24 (2H, m), 0.97 (2H, m). 700

method 5: RT: 2.59 min, MI: 414.29 [M + H] 1H NMR (500 MHz, DMSO) 8.94(1H, s), 8.18 (1H, d), 8.06 (1H, s), 7.58 (1H, s), 7.46 (1H, dd), 7.39(1H, s), 3.74-3.63 (4H, m), 2.88 (4H, m), 2.62-2.60 (2H, m), 2.09 (6H,s), 1.24- 1.22 (2H, m), 1.01-0.99 Bicyclo[1.1.1]pent- 1-yl-[4-(5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-amine (4H, m). 701

method 5: RT: 3.76 min, MI: 442.33 [M + H] 1H NMR (500 MHz, DMSO) 8.98(1H, d), 8.94 (1H, s), 8.11 (1H, s), 8.06 (1H, d), 7.81 (2H, d), 7.42(1H, t), 7.28 (2H, t), 6.95 (1H, t), 3.73 (4H, s, br), 2.82 (4H, s, br),2.63-2.57 (1H, m), 1.27-1.25 (2H, [4-(5-Cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)-3- fluoro-pyridin-2-yl]- phenyl-amine m),1.03-1.02 (2H, m). 702

method 5: RT: 2.35 min, MI: 474 [M + H] 1H NMR (DMSO, 500 MHz) 9.04 (1H,s), 8.98 (1H, s), 8.18 (1H, d), 8.15 (1H, s), 7.84 (1H, s), 7.71 (1H,dd), 7.31 (1H, m), 7.19 (2H, t), 4.18 (2H, m), 4.01 (2H,[4-(5-Cyclopropyl- 4-[1,4]diazepan-1- yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6- difluoro-phenyl)- amine m), 3.47 (2H, m), 3.16 (2H,m), 2.35 (1H, m), 2.06 (2H, m), 1.26 (2H, m), 0.98 (2H, m). 703

method 5: RT: 2.19 min, MI: 420.29 [M + H] 1H NMR (500 MHz, DMSO) 8.93(1H, s), 8.11 (1H, d), 9.06 (1H, s), 7.48 (1H, s), 7.44 (1H, dd), 7.14(1H, d), 5.34-5.20 (1H, m), 4.85 (1H, m, br), 3.77-3.56 (5H, m, br),2.84 (4H, s), 2.62-2.59 (2H, m), 2.36- (+/−)cis-[4-(5- Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d] pyrimidin-2-yl)- pyridin-2-yl]-(3-fluoro-cyclobutyl)- amine 2.27 (2H, m), 1.26-1.23 (2H, m), 1.03-1.00(2H, m). 704

461.54 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.39 (s, 1 H) 8.98 (s, 1 H) 8.67(s, 1 H) 8.35 (d, J = 5.3 Hz, 1 H) 8.22 (d, J = 2.5 Hz, 1 H) 8.10 (s, 1H) 7.94 (ddd, J = 10.7, 8.3, 2.6 Hz, 1 H) 7.84 (dd, J = 5.1, 1.4 Hz, 1H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5- difluoro-pyridin-2- yl)-amine 3.58-3.86 (m, 4 H)2.85 (br. s., 4 H) 2.73-52 (m, 1H) 1.22-1.31 (m, 2 H) 0.99-1.07 (m, 2 H)705

461.63 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3,5- difluoro-pyridin-4- yl)-amine 706

506.53 (M + H) (dmso-d6) 9.05 (s, 1H), 8.99 (br s, 1H), 8.22- 8.16 (m,2H), 8.13 (d, J = 10.0 Hz, 1H), 7.89 (s, 1H), 7.65 (app d, J = 7.2 Hz,2H), 7.61 (dd, J = 5.4; 1.4 Hz, 1H), 7.48- 7.35 (m, 3H), 6.23 (quint, J= 9.2 Hz, 1H), [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,2,2- trifluoro-1-phenyl-ethyl)-amine 4.51 (br s, exch. H's), 3.91 (br s, 6H), 2.74- 2.64 (m,1H), 1.30-1.22 (m, 2H), 1.12-1.04 (m, 2H) 707

516 (M + H) 1-{5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-3- carboxylicacid methyl amide 708

460 (M + H) {4-[4-(3-Amino- pyrrolidin-1-yl)-5- cyclopropyl- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6- difluoro-phenyl)- amine 709

482 (M + H) 1H NMR (400 MHz, DMSO-d6) 9.52 (1 H, br. s.), 9.06 (1 H, s),8.76- 9.04 (2 H, m), 8.31 (1 H, d, J = 5.3 Hz), 8.19 (1 H, s), 7.97 (1H, s), 7.72 (1H, dd, J = 5.5, 1.3 Hz), 7.65 (2 H, d, J = 8.5 Hz), 7.21(2 H, d, J = 8.5 Hz), 3.78-3.99 (4 H, m), 3.52 (2 H, s), 3.33 (4 H, br.s.), 2.65-2.78 (1 H, {4-[4-(5- Cyclopropyl-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-ylamino]- phenyl}-acetic acidm), 1.19-1.34 (2 H, m), 0.99-1.14 (2 H, m) 710

521.78 (CDCl₃) 9.06 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.07 (s, 1H),8.01 (s, 1H), 7.79 (dd, J = 5.2; 1.3 Hz, 1H), 7.23 (app t, J = 8.0 Hz,1H), 7.05- 7.02 (m, 1H), 7.00-6.98 (m, 1H), 6.93 (dd, J = 8.0; 1.6 Hz,1H), 6.65 (dd, J = 8.0; 2.0 Hz, 1H), [4-(5-Cyclopropyl-4-piperidin-1-yl- pyrido[3,4d]pyrimidin- 2-yl)-pyridin-2-yl]-[3-(4-methyl- piperazin-1-yl)- phenyl]-amine 3.70 (br s, 4H), 3.28-3.24 (m, 4H), 2.66-2.62 (m, 1H), 2.61-2.56 (m, 4H), 2.35 (s, 3H), 1.69br s, 6H), 1.26-1.18 (m, 2H), 1.00-0.95 (m, 2H) 711

480.59 3-{4-[5- Cyclopropyl-4- ((3R,4S)-3,4- dihydroxy- piperidin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-ylamino}- benzonitrile 712

480 (M + H) 1H NMR (400 MHz, DMSO-d6) 9.06 (1H, s), 8.88 (2 H, br. s.),8.13- 8.25 (2 H, m), 7.89 (1 H, br. s.), 7.63 (1 H, br. s.), 7.33 (1 H,d, J = 7.3 Hz), 7.23 (1 H, t, J = 7.5 Hz), 6.92 (1 H, t, J = 7.3 Hz),6.86 (1H, d, J = 8.3 Hz), Chroman-4-yl-[4-(5- cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-amine 5.21(1 H, br. s.), 4.18- 4.31 (3 H, m), 3.83- 3.94 (4 H, m), 3.31 (4 H, br.s.), 2.64-2.72 (1 H, m), 2.13-2.26 (1 H, m), 2.00-2.13 (1 H, m),1.20-1.33 (2 H, m), 1.01-1.12 (2 H, m) 713

502 (M + H) N-(1-{5- Cyclopropyl-2-[2- (2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- pyrrolidin-3-yl)-acetamide 714

484.25 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- fluoro-4-isopropyl- phenyl)-amine715

470 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(5- ethyl-2-fluoro- phenyl)-amine 716

484.2 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- fluoro-5-isopropyl- phenyl)-amine717

470.2 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(4- ethyl-2-fluoro- phenyl)-amine 718

488 (M + H) 1H NMR (500 MHz, DMSO) 8.92 (1H, s), 8.75 (1H, s), 8.15 (1H,d), 8.08 (1H, s), 7.74 (1H, s), 7.64 (1H, dd), 7.34-7.24 (1H, m), 7.16(2H, t), 3.91-3.52 (4H, m, br), 2.85 (2H, s), {4-[5-Cyclopropyl-4-(3,3-dimethyl- piperazin-1-yl)- pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6- difluoro-phenyl)- amine 2.50-2.45 (1H, m), 1.23-1.22 (2H, m), 1.08-0.98 (6H, m), 0.78 (2H, s, br). 719

470 (M + H) 1H NMR (500 MHz, DMSO) 9.32 (1H, s), 8.93 (1H, s), 8.28 (1H,d), 8.08 (1H, s), 7.85 (1H, s), 7.76-7.73 (2H, m), 7.66 (1H, d), 7.11(2H, t), 3.95-3.55 (4H, m), 2.87 (2H, m, br), {4-[5-Cyclopropyl-4-(3,3-dimethyl- piperazin-1-yl)- pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2-yl}-(4- fluoro-phenyl)- amine 2.53 (1H, m), 1.24-1.22 (2H, m),1.06-0.78 (9H, m). 720

537.67 (R)-1-(5- Cyclopropyl-2-{2- [3-(4-methyl- piperazin-1-yl)-phenylamino]- pyridin-4-yl}- pyrido[3,4- d]pyrimidin-4-yl)-piperidin-3-ol 721

537.71 [(R)-1-(5- Cyclopropyl-2-{2- [3-(4-methyl- piperazin-1-yl)-phenylamino]- pyridin-4-yl}- pyrido[3,4- d]pyrimidin-4-yl)-pyrrolidin-3-yl]- methanol 722

537.7 [(S)-1-(5- Cyclopropyl-2-{2- [3-(4-methyl- piperazin-1-yl)-phenylamino]- pyridin-4-yl}- pyrido[3,4- d]pyrimidin-4-yl)-pyrrolidin-3-yl]- methanol 723

530 (M + H) 1-{5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-4- carboxylicacid ethylamide 724

501.57 (MH)+ (6-Cyclopropyl-2,4- difluoro-pyridin-3- yl)-[4-(5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-amine; bis-trifluoroacetic salt 725

483.61 (MH)+ (6-Cyclopropyl-2- fluoro-pyridin-3-yl)-[4-(5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-amine; bis-trifluoroacetic acid salt 726

502 (M + H) 1-{5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- pyrrolidine-3- carboxylicacid methylamide 727

523.66 (M + H)+ (S)-1-(5- Cyclopropyl-2-{2- [3-(4-methyl-piperazin-1-yl)- phenylamino]- pyridin-4-yl}- pyrido[3,4-d]pyrimidin-4-yl)- pyrrolidin-3-ol 728

537.73 (M + H)+ 1-(3-{4-[5- Cyclopropyl-4-(4- methyl-piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-ylamino}-phenyl)-piperidin-4- ol 729

523.70 (M + H)+ 1-{5-Cyclopropyl-2- [2-(3-piperazin-1-yl- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidin-4-ol 730

456 (M + H) 1H NMR (400 MHz, DMSO-d6) 9.08 (4 H, s), 8.22(1 H, s), 8.08(1 H, d, J = 6.5 Hz), 8.04 (1 H, br. s.), 7.75 (1 H, s), 7.70 (1 H, dd,J = 6.5, 1.3 Hz), 7.49 (1 H, s), 5.06 (1 H, br. s.), 3.6-3.9 (8 H, m),3.32 (4 H, br. s.), 2.62- [4-(5-Cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-[1-(1- methyl-1H-pyrazol-4-yl)-ethyl]-amine 2.68 (1H, m), 1.55 (3 H, d, J = 6.8 Hz), 1.21-1.31 (2H, m), 1.05-1.12 (2 H, m) 731

528.63 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2- fluoro-6-morpholin-4-yl-pyridin-3-yl)- amine 732

526 1-{5-Cyclopropyl-2- [2-(1-piperidin-4- ylmethyl-1H-pyrazol-4-ylamino)- pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}-piperidin-4-ol 733

— 487.15 4-((R)-3- Benzyloxymethyl- piperazin-1-yl)-2-(2-chloro-pyridin-4- yl)-5-cyclopropyl- pyrido[3,4- d]pyrimidine 734

464.2 (3-Cyclopropyl- phenyl)-[4-(5- cyclopropyl-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-amine 735

585 (M + H) (1-{5-Cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidin-4-yl)-(4-methyl-piperazin-1- yl)-methanone 736

573 (M + H) 1-{5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-4- carboxylicacid (2- dimethylamino- ethyl)-amide 737

537.72 (M + H) (S)-1-(5- Cyclopropyl-2-{2- [3-(4-methyl-piperazin-1-yl)- phenylamino]- pyridin-4-yl}- pyrido[3,4-d]pyrimidin-4-yl)- piperidin-3-ol 738

523.68 (M + H)+ (R)-1-(5- Cyclopropyl-2-{2- [3-(4-methyl-piperazin-1-yl)- phenylamino]- pyridin-4-yl}- pyrido[3,4-d]pyrimidin-4-yl)- pyrrolidin-3-ol 739

560 (M + H) 1-{5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-4- carboxylicacid (2- methoxy-ethyl)- amide 740

485 (M + H) 1H NMR (400 MHz, DMSO-d6) 9.13 (1 H, s), 9.02-9.09 (1 H, m),8.75 - 8.98 (2 H, m), 8.39 (1 H, br. s.), 8.17- 8.31 (2 H, m), 7.74-8.06 (2 H, m), 3.84- 4.04 (4 H, m), 3.36 (4 H, br. s.), 2.71 (1 H, br.s.), 1.19-1.33 (2 H, m), 1.04-1.16 (2 H, m) 4-[4-(5- Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-ylamino]-3,5-difluoro- benzonitrile 741

571 (M + H) (1-{5-Cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidin-4-yl)-piperazin-1-yl- methanone 742

467 (M + H) 1H NMR (400 MHz, DMSO-d6) 9.72 (1 H, s), 9.07 (1 H, s),8.78-9.03 (2 H, m), 8.41 (1 H, d, J = 5.3 Hz), 8.19 (1 H, s), 8.01 (1 H,s), 7.69-7.89 (6 H, m), 7.14 (1 H, br. s.), 3.94 (4 H, br. s.), 3.34 (4H, br. s.), 2.64- 2.77 (1 H, m), 1.20- 4-[4-(5- Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-ylamino]-benzamide 1.32 (2 H, m), 1.01- 1.13 (2 H, m) 743

465.56 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl-amine 744

559 (M + H) 1-{5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidine-4- carboxylicacid (2- methylamino-ethyl)- amide 745

481.53 6-{4-[5- Cyclopropyl-4- ((cis)-3,4- dihydroxy- piperidin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-ylamino}- pyridine-2-carbonitrile 746

450.55 (M + H)+ 6-[4-(5- Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-ylamino]- pyridine-2- carbonitrile 747

589.70 (M + H)+ 1-(5-Cyclopropyl-2- {2-[3-(4-methyl- piperazin-1-yl)-phenylamino]- pyridin-4-yl}- pyrido[3,4- d]pyrimidin-4-yl)-3,3-difluoro- piperidine-4,4-diol 748

461.51 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(4,6- difluoro-pyridin-3- yl)-amine 749

461.50 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(2,5- difluoro-pyridin-3- yl)-amine 750

425.54 (M + H)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- pyridin-2-yl-amine 751

553.28 (CDCl₃) 9.07 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 8.08 (br s, 1H),8.02 (s, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.24 (dd, J = 8.4 Hz, 1H)), 7.06(br s, 1H), 6.98 (br s, 1H), 6.82 (br d, J = 7.08 Hz, 1H), 6.69 (dd, J =8.4; 1.9 Hz, 1H), 3.95 (m, 5H), 3.55 (m, br (3R,4S or 3R,4S)-1-(5-Cyclopropyl-2- {2-[3-(4-methyl- piperazin-1-yl)- phenylamino]-pyridin-4-yl}- pyrido[3,4- d]pyrimidin-4-yl)- piperidine-3,4-diol Singleenantiomer, s, 1H), 3.25 (br s, 5H), unassigned 2.60 (m, 5H), 2.34 (s,3H), 1.91 (m, 1H), 1.7 br s (exch. H's), 1.24 (m, 2H), 0.97 (m, 2H) 752

553.29 (CDCl₃) 9.07 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 8.08 (br s, 1H),8.02 (s, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.24 (dd, J = 8.4 Hz, 1H)), 7.06(br s, 1H), 6.98 (br s, 1H), 6.82 (br d, J = 7.08 Hz, 1H), 6.69 (dd, J =8.4; 1.9 Hz, 1H), 3.95 (m, 5H), 3.55 (m, br (3R,4S or 3R,4S)-1-(5-Cyclopropyl-2- {2-[3-(4-methyl- piperazin-1-yl)- phenylamino]-pyridin-4-yl}- pyrido[3,4- d]pyrimidin-4-yl)- piperidine-3,4-diol Singleenantiomer, s, 1H), 3.25 (br s, 5H), unassigned 2.60 (m, 5H), 2.34 (s,3H), 1.91 (m, 1H), 1.7 br s (exch. H's), 1.24 (m, 2H), 0.97 (m, 2H) 753

553.3 (CDCl₃) 9.16 (s, 1H), 8.94 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 8.08(s, 1H), 7.91 (s, 1H), 7.66 (dd, J = 5.2; 1.0 Hz, 1H), 7.34 (app t, J =2.0 Hz, 1H), 7.22 (dd, J = 8.0; 1.1 Hz, 1H), 7.11 (app t, J = 8.1 Hz,1H), 6.52 (dd, J = 8.2; 1.8 Hz, 1H), (3S,4S or 3R,4R)-1-(5-Cyclopropyl-2- {2-[3-(4-methyl- piperazin-1-yl)- phenylamino]-pyridin-4-yl}- pyrido[3,4- d]pyrimidin-4-yl)- piperidine-3,4-diol Singleenantiomer, 5.28-4.67 (m, 2H), 4.28- unassigned 3.71 (m, 2H), 3.50 (brs, 1H), 3.15-3.11 (m, 4H), 2.61-2.53 (m, 1H), 2.49- 2.45 (m, 4H), 2.23(s, 3H), 2.18-1.73 (m, 2H), 1.44-1.11 (m, 3H), 1.10- 0.90 (m, 2H) 754

553.3 (CDCl₃) 9.16 (s, 1H), 8.94 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 8.08(s, 1H), 7.91 (s, 1H), 7.66 (dd, J = 5.2; 1.0 Hz, 1H), 7.34 (app t, J =2.0 Hz, 1H), 7.22 (dd, J = 8.0; 1.1 Hz, 1H), 7.11 (app t, J = 8.1 Hz,1H), 6.52 (dd, J = 8.2; 1.8 Hz, 1H), (3S,4S or 3R,4R)-1-(5-Cyclopropyl-2- {2-[3-(4-methyl- piperazin-1-yl)- phenylamino]-pyridin-4-yl}- pyrido[3,4- d]pyrimidin-4-yl)- piperidine-3,4-diol Singleenantiomer, 5.28-4.67 (m, 2H), 4.28- unassigned 3.71 (m, 2H), 3.50 (brs, 1H), 3.15-3.11 (m, 4H), 2.61-2.53 (m, 1H), 2.49- 2.45 (m, 4H), 2.23(s, 3H), 2.18-1.73 (m, 2H), 1.44-1.11 (m, 3H), 1.10- 0.90 (m, 2H) 755

449 (M + H) {4-[5-Cyclopropyl- 4-(2-methylamino- ethoxy)-pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6- difluoro-phenyl)- amine 756

443 (M + H)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(4- fluoro-pyridin-2-yl)- amine 757

475 (M + H) {4-[5-Cyclopropyl- 4-(piperidin-4- yloxy)-pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6- difluoro-phenyl)- amine 758

442 (M + H) 1H NMR (400 MHz, DMSO-d6) 9.08 (1 H, s), 8.78-9.01 (2 H, m),8.22 (1 H, s), 8.11 (1 H, d, J = 6.3 Hz), 7.90-8.05 (1 H, m), 7.76 (1 H,s), 7.68 (1 H, d, J = 6.8 Hz), 7.50 (1 H, s), 4.45 (2 H, br. s.), 3.88(4 H, br. s.), [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(1- methyl-1H-pyrazol-4-ylmethyl)-amine 3.83 (3 H, s), 3.31 (4 H, br. s.), 2.63-2.70 (1 H, m),1.19-1.34 (2 H, m), 1.02-1.15 (2 H, m) 759

method 5: RT: 2.56 min, MI: 452 [M + H] 1H NMR (DMSO, 500 MHz) 8.99 (1H,s), 8.17 (4H, m), 7.55 (1H, m), 7.44 (1H, m), 7.28 (4H, m), 7.20 (1H,m), 6.89 (1H, m), 3.75 (4H, s), 3.56 (6H, m), 2.88 (2H, m), 2.66 (1H,m), 1.25 (2H, m), 1.03 (2H, m). [4-(5-Cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]- phenethyl-amine 760

507.35 (M + H) [4-(5-Cyclopropyl- 4-pyrrolidin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[3-(4- methyl-piperazin-1-yl)-phenyl]-amine 761

493.39 (M + H) [4-(4-Azetidin-1-yl- 5-cyclopropyl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[3-(4- methyl-piperazin-1-yl)-phenyl]-amine 762

method 5: RT: 3.12 min, MI: 473 [M + H] [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(3-fluoro-6-methoxy- pyridin-2-yl)-amine 763

method 5: RT: 3.03 min, MI: 489 [M + H] {4-[5-Cyclopropyl-4-(3,5-dimethyl- piperazin-1-yl)- pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2-yl}-(3,6- difluoro-pyridin-2- yl)-amine 764

method 5: RT: 4.20 min, MI: 478.39 [M + H] 1H NMR (500 MHz, DMSO) 8.93(1H, s), 8.75 (1H, s), 8.11 (1H, d), 8.10 (1H, s), 7.50 (1H, d),7.26-7.23 (1H, m), 7.15 (2H, t), 4.09- 4.08 (2H, m), 3.67 (4H, s, br),2.80 (4H, s, br), 2.58-2.54 (1H, m), 1.26- [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-5- fluoro-pyridin-2-yl]-(2,6-difluoro- phenyl)-amine 1.24 (2H, m), 1.03-1.01 (2H, m). 765

method 5: RT: 4.58 min, MI: 460.40 [M + H] 1H NMR (500 MHz, DMSO) 9.31(1H, s), 8.94 (1H, s), 8.23 (1H, d), 8.18 (1H, s), 8.12 (1H, s), 7.67(2H, dd), 7.58 (1H, 7.11 (2H, t), 3.69 (4H, s, br), 2.88 (4H, s, br),2.60-2.56 (1H, m), 1.26-1.24 (2H, [4-(5-Cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)-5- fluoro-pyridin-2-yl]-(4-fluoro-phenyl)- amine m), 1.03-1.02 (2H, m). 766

493.39 (M + H) [4-(5-Cyclopropyl- 4-pyrrolidin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3- piperazin-1-yl- phenyl)-amine 767

479.29 (M + H) [4-(4-Azetidin-1-yl- 5-cyclopropyl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3- piperazin-1-yl- phenyl)-amine 768

510.25 N-{4-[4-((R)-3- Benzyloxymethyl- piperazin-1-yl)-5- cyclopropyl-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}- acetamide 769

516 {4-[5-Cyclopropyl- 4-((R)-3- methanesulfonyl- methyl-piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}- phenyl-amine 770

482 N-{4-[5- Cyclopropyl-4-((R)- 3-methanesulfonyl- methyl-piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}- acetamide 771

534.2 {4-[5-Cyclopropyl- 4-((R)-3- methanesulfonyl- methyl-piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(4- fluoro-phenyl)-amine 772

552.2 {4-[5-Cyclopropyl- 4-((R)-3- methanesulfonyl- methyl-piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6- difluoro-phenyl)-amine 773

508.2 Cyclopropanecar- boxylic acid {4-[5- cyclopropyl-4-((R)-3-methanesulfonyl- methyl-piperazin-1- yl)-pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-amide 774

479 (M + H)+ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.08 (s, 1 H) 8.96-9.02(m, 1 H) 8.89-9.13 (m, 3 H) 8.43-8.53 (m, 1 H) 8.19 (s, 1 H) 8.00 (dd, J= 5.1, 1.4 Hz, 1 H) 7.01 (dt, J = 9.3, 3.0 Hz, 1 H) 3.77- 4.13 (m, 4 H)3.28- [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3,4,6- trifluoro-pyridin-2- yl)-amine3.41 (m, 4 H) 2.63-2.74 (m, 1 H) 1.20-1.33 (m, 2 H) 1.04-1.13 (m, 2 H)775

448 (M + H) N-{5-Cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- N′-methyl-ethane-1,2-diamine 776

462 (M + H) N-{5-Cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- N′,N′-dimethyl-ethane-1,2-diamine 777

509.26 (M + H) 1-(5-Cyclopropyl-2- {2-[3-(4-methyl- piperazin-1-yl)-phenylamino]- pyridin-4-yl}- pyrido[3,4- d]pyrimidin-4-yl)-azetidin-3-ol 778

495.29 (M + H) 1-{5-Cyclopropyl-2- [2-(3-piperazin-1-yl- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- azetidin-3-ol 779

456.22 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(1- isopropyl-1H- pyrazol-3-yl)-amine780

456.24 (M + H) [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(1- ethyl-5-methyl-1H-pyrazol-3-yl)-amine 781

538.36 (M + H) (R)-1-(5- Cyclopropyl-2-{2- [6-(4-methyl-piperazin-1-yl)- pyridin-2-ylamino]- pyridin-4-yl}- pyrido[3,4-d]pyrimidin-4-yl)- piperidin-3-ol 782

523.66 (M + H) [4-(5-Cyclopropyl- 4-piperidin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[6-(4- methyl-piperazin-1-yl)-pyridin-2-yl]- amine 783

475.19 (MH)+ [4-(5-Cyclobutyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3,5- difluoro-pyridin-2- yl)-amine 784

457.25 (MH)+ [4-(5-Cyclobutyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3- fluoro-pyridin-2-yl)- amine 785

457.29 (M + H)+ [4-(5-Cyclobutyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(4- fluoro-pyridin-2-yl)- amine 786

593.28 (M + H)+ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.09 (s, 1 H) 9.15 (s,1 H) 8.79-8.96 (m, 3 H) 8.48 (d, J = 5.3 Hz, 1 H) 8.00 (dd, J = 5.1, 1.4Hz, 1 H) 7.02 (dt, J = 9.5, 3.0 Hz, 1 H) 4.17-4.32 (m, 1 H) 3.81-3.92(m, 4 H) 3.19- [4-(5-Cyclobutyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3,4,6- trifluoro-pyridin-2- yl)-amine3.39 (m, 4 H) 1.86- 2.44 (m, 6 H) 787

method 5: RT: 3.09 min, MI: 488 [M + H] {4-[5-Cyclopropyl-4-(3,5-dimethyl- piperazin-1-yl)- pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6- difluoro-phenyl)- amine 788

method 5: RT: 4.07 min, MI: 485 [M + H] (R)-4-{5- Cyclopropyl-2-[2-(2,6-difluoro- phenylamino)- pyridin-4-yl]- pyrido[3,4-d]pyrimidin-4-yl}- piperazine-2- carbonitrile 789

457 (M + H) {4-[5-Cyclopropyl- 4-(1,2,3,6- tetrahydro-pyridin-4-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6-difluoro-phenyl)- amine 790

474 (M + H) {5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidin-4-yl-amine 791

491 (M + H) {4-[5-Cyclopropyl- 4-(piperidin-4- ylsulfanyl)- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6- difluoro-phenyl)- amine 792

491 (M + H) {4-[5-Cyclopropyl- 4-(piperidin-4- ylsulfanyl)- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6- difluoro-phenyl)- amine 793

539.5 (M + H) (3S,4S)-1-(5- Cyclopropyl-2-{2- [3-(4-methyl-piperazin-1-yl)- phenylamino]- pyridin-4-yl}- pyrido[3,4-d]pyrimidin-4-yl)- pyrrolidine-3,4-diol 794

454.25 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(1- cyclopropyl-1H- pyrazol-4-yl)-amine795

498.25 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[1- (tetrahydro-pyran-4-yl)-1H-pyrazol-4- yl]-amine 796

482.2 (1-Cyclopentyl-1H- pyrazol-4-yl)-[4-(5- cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-amine 797

476 (M + H) N-{5-Cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- N,N′,N′-trimethyl-ethane-1,2-diamine 798

method: 5, RT: 2.78 min, MI: 489 [M + H] 1H NMR (DMSO, 500 MHz) 9.70(1H, s), 9.17 (1H, s, br), 9.11 (1H, s), 8.69 (1H, s), 8.46 (1H, m),7.98 (1H, m), 7.85 (1H, m), 6.71 (1H, m), 4.28 (1H, m), 4.26 (1H, m),4.06 (1H, m), {4-[5-Cyclobutyl-4- ((S)-3-methyl- piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(3,6- difluoro-pyridin-2-yl)-amine 3.91 (1H, m), 3.79 (1H, m), 3.65 (1H, m), 3.23 (1H, m), 3.06(1H, m), 2.52 (3H, s), 2.16 (2H, m), 2.21 (2H, m), 2.09 (1H, m), 1.91(1H, m). 799

method 5: RT: 2.72 min, MI: 475 [M + H] 1H NMR (DMSO, 500 MHz) 9.70 (1H, s), 9.14 (1H, s, br), 9.02 (1H, s), 8.80 (1H, d), 8.46 (1H, m), 7.97(1H, m), 7.86 (1H, m), 6.71 (1H, m), 4.25 (1H, m), 3.86 (4H, m), 3.58(4H, m), 2.80 (2H, m), 2.21 (2H, [4-(5-Cyclobutyl-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(3,6- difluoro-pyridin-2-yl)-amine m), 2.08 (1H, m), 1.93 (1H, m). 800

method 5: RT: 1.62 min, MI: 457 [M + H] {4-[5-Cyclopropyl-4-((S)-3-methyl- piperazin-1-yl)- pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2-yl}-(3- fluoro-pyridin-2-yl)- amine 801

method 5: RT: 2.59 min, MI: 477 [M + H] (6-Chloro-3-fluoro-pyridin-2-yl)-[4-(5- cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-amine 802

method 5: RT: 2.57 min, MI: 489.49 [M + H] 1H NMR (500 MHz, DMSO) 8.93(1H, s), 8.06 (1H, s), 8.01 (1H, d), 7.92-7.84 (1H, m), 7.66 (1H, s),7.39 (1H, d), , 7.33 (1H, d), 7.12- 7.07 (1H, m), 5.42 (1H, t, br),3.83-3.57 (4H, m, br), 3.16 (1H, s, br), 2.84 (4H, s, br), 2.61 (1H, m,br), 1.45 (3H, d), 1.25- [4-(5-Cyclopropyl- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-[(R)-1- (3,6-difluoro-pyridin-2-yl)-ethyl]- amine 1.22 (2H, m), 1.03-1.01 (2H, m). 803

490 (M + H) N-{5-Cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- N′,N′-dimethyl-butane-1,4-diamine 804

535.50 (M + H) [4-(4-Azepan-1-yl- 5-cyclopropyl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[3-(4- methyl-piperazin-1-yl)-phenyl]-amine 805

458.36 (M + H) 1-{5-Cyclopropyl-2- [2-(6-fluoro-pyridin-2-ylamino)-pyridin- 4-yl]-pyrido[3,4- d]pyrimidin-4-yl}- piperidin-4-ol806

458.20 (M + H) (R)-1-{5- Cyclopropyl-2-[2- (6-fluoro-pyridin-2-ylamino)-pyridin-4- yl]-pyrido[3,4- d]pyrimidin-4-yl}- piperidin-3-ol807

method 5: RT: 2.88 min, MI: 493 [M + H] 1H NMR (DMSO, 500 MHz) 9.74 (1H,s), 9.13 (1H, s, br), 8.80 (2H, dd), 8.42 (1H, d), 8.26 (1H, m), 7.94(1H, d), 4.23 (1H, m), 3.84 (4H, m), 3.25 (4H, m), 2.38 (2H, m), 2.21(2H, m), 2.10 (1H, [4-(5-Cyclobutyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(3,5,6- trifluoro-pyridin-2- yl)-aminem), 1.89 (1H, m). 808

method 5: RT: 2.90 min, MI: 506 [M + H] 1H NMR (DMSO, 500 MHz) 9.76 (1H,s), 9.17 (1H, s, br), 9.11 (1H, s), 8.70 (1H, s), 8.44 (1H, m), 8.28(1H, m), 7.95 (1H, m), 4.27 (1H, m), 4.26 (1H, m), 4.06 (1H, m), 3.91(1H, m), 3.79 (1H, m), 3.65 {4-[5-Cyclobutyl-4- ((S)-3-methyl-piperazin-1-yl)- pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(3,5,6-trifluoro-pyridin-2- yl)-amine (1H, m), 3.23 (1H, m), 3.06 (1H, m), 2.53(3H, s), 2.16 (2H, m), 2.16 (2H, m), 2.07 (1H, m), 1.89 (1H, m). 809

507.19 (MH)+ [4-(5-Cyclobutyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(5- trifluoromethyl-pyridin-2-yl)-amine 810

416.26 (M + H) ((R)-1-Cyclopropyl- ethyl)-[4-(5- cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-amine 811

458.29 (M + H) ((R)-1-Cyclohexyl- ethyl)-[4-(5- cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-amine 812

483.21 (MH)+ (5-Cyclopropyl-3- fluoro-pyridin-2-yl)-[4-(5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-amine 813

method 5: RT: 2.60 min, MI: 515.51 [M + H] 1H NMR (500 MHz, DMSO, 90°C.) 9.07 (1H, s), 8.23 (1H, s), 8.13 (1H, d), 7.76 (1H, s), 7.57 (1H,dd), 4.22-4.19 (2H, m), 4.11-4.06 (1H, m), 3.97 (4H, t, br), 3.35 (4H,t, br), 3.15-3.08 (2H, m), 2.70-2.66 (1H, 1-{4-[4-(5- Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-ylamino]-piperidin-1-yl}-2,2- dimethyl-propan-1- one m), 2.05-2.03 (2H, m),1.52-1.42 (2H, m), 1.29- 1.27 (2H, m), 1.26 (9H, s), 1.05-1.03 (2H, m).814

method 5: RT: 2.43 min, MI: 513.41 [M + H] 1H NMR (500 MHz, DMSO, 90°C.) 9.07 (1H, s), 8.23 (1H, s), 8.10 (1H, d), 7.81 (1H, s), 7.58 (1H,dd), 3.97 (4H, t, br), 3.86-3.81 (1H, m), 3.34 (4H, t, br), 3.20 (2H,q), 3.01-2.98 (2H, m), 2.70-2.67 (1H, m), [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-[1-(2,2,2-trifluoro- ethyl)-piperidin-4- yl]-amine 2.61 (2H, t), 2.00-1.97(2H, m), 1.66-1.57 (2H, m), 1.30-1.25 (2H, m), 1.05-1.03 (2H, m). 815

method 5: RT: 3.71 min, MI: 507.41 [M + H] 1H NMR (500 MHz, DMSO, 90°C.) 9.07 (1H, s), 8.71 (1H, s), 8.43 (1H, d), 8.26 (1H, s), 8.12 (1H,q), 7.98 (1H, dd), 4.02 (2H, t, br), 3.95 (2H, s), 3.38 (2H, t),2.56-2.54 (1H, m), 1.31 {4-[5-Cyclopropyl- 4-(3,3-dimethyl-piperazin-1-yl)- pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(3,5,6-trifluoro-pyridin-2- yl)-amine (6H, s), 1.30-1.27 (2H, m), 1.02 (2H,dd). 816

method 5: RT: 2.06 min, MI: 509.44 [M + H] 1H NMR (500 MHz, DMSO, 90°C.) 9.07 (1H, s), 8.22 (1H, s), 8.14 (1H, d), 7.74 (1H, s), 7.57 (1H,dd), 3.97 (4H, t, br), 3.65-3.60 (2H, m), 3.35 (4H, t, br), 3.04- 2.97(2H, m), 2.90 (3H, s), 2.71-2.65 (1H, m), [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(1-methanesulfonyl- piperidin-4-yl)- amine 2.12-2.07 (2H, m), 1.68- 1.59(2H, m), 1.29-1.26 (2H, m), 1.05-1.03 (2H, m). 817

508.05 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[1-(2- fluoro-phenyl)-1H-pyrazol-4-yl]-amine 818

526.2 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[1- (2,6-difluoro- phenyl)-1H-pyrazol-4-yl]-amine 820

544.2 [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[1- (2,4,6-trifluoro-phenyl)-1H-pyrazol- 4-yl]-amine 821

494.25 (M + H) 1-{5-Cyclopropyl-2- [2-(2-methyl-2,3- dihydro-1H-isoindol-5-ylamino)- pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}-piperidin-4-ol 822

486 (M + H − NH3) 1H NMR (400 MHz, DMSO-d6) 9.10 (1 H, s), 8.93 (3 H, d,J = 7.8 Hz), 8.45-8.51 (1 H, m), 8.22 (1H, s), 8.03 (1 H, dd, J = 7.7,1.9 Hz), 7.97 (1 H, ddd, J = 10.6, 8.8, 2.9 Hz), 7.86 (1 H, dt, J = 8.5,1.5 Hz), 4.00 (4 H, br. s.), 3.40 (4 H, br. 4-[4-(5- Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-ylamino]-3,5-difluoro- benzamide s.), 2.65-2.78 (1 H, m), 1.26-1.36 (2 H, m),1.07-1.16 (2 H, m) 823

442 (M + H) 1H NMR (400 MHz, DMSO-d6) 9.10 (1 H, s), 8.97 (2 H, br. s.),8.25 (1 H, s), 8.08 (2 H, d, J = 6.3 Hz), 7.70 (1 H, d, J = 5.8 Hz),4.19-4.47 (4 H, m), 3.66 (2 H, br. s.), 3.34 (4 H, br. s.), 2.65- 2.76(1 H, m), 2.32- (1S,2S,4R)- Bicyclo[2.2.1]hept- 2-yl-[4-(5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-amine 2.39 (2 H, m), 1.85- 1.96 (1H, m), 1.43- 1.69 (4H,m), 1.05- 1.41 (8 H, m) 824

442 (M + H) 1H NMR (400 MHz, DMSO-d6) 9.09 (1 H, s), 8.82-9.05 (2 H, m),8.24 (1 H, s), 8.08 (2 H, d, J = 6.8 Hz), 7.63-7.74 (1 H, m), 4.02-4.30(4 H, m), 3.63-3.67 (2 H, m), 3.34 (4 H, br. s.), 2.66-2.71 (1 H, m),(1R,2R,4S)- Bicyclo[2.2.1]hept- 2-yl-[4-(5- cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-amine2.26-2.41 (2 H, m), 1.90 (1 H, m), 1.54 (4 H, br. s.), 1.06-1.42 (8 H,m) 825

505.24 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(5- cyclopropyl- [1,2,4]triazolo[1,5-a]pyridin-2-yl)- amine 826

463 (M + H) {4-[5-Cyclopropyl- 4-(2- dimethylamino- ethoxy)-pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6- difluoro-phenyl)- amine 827

493.19 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(5- trifluoromethyl-pyridin-2-yl)-amine 828

method 5: RT: 2.69 min, MI: 507 [M + H] 1H NMR (DMSO, 400 MHz, 90° C.)9.08 (1H, s), 8.67 (1H, s), 8.43 (1H, dd), 8.23 (1H, s), 8.12 (1H, m),7.97 (1H, m), 4.39 (2H, m), {4-[5-Cyclopropyl- 4-((3R,5S)-3,5-dimethyl-piperazin- 1-yl)-pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2-yl}-(3,5,6- 3.23 (2H, m), 2.67 (1H, trifluoro-pyridin-2- m),1.34 (6H, m), 1.26 yl)-amine (2H, m), 1.15 (2H, m), 1.06 (2H, m). 829

method 5; RT: 3.32 min, MI: 486.42 [M + H] 1H NMR (500 MHz, DMSO, 90°C.) 9.05 (1H, s), 8.23 (1H, s), 8.20 (1H, d), 7.76 (1H, s), 7.69 (1H,dd), 7.32-7.27 (2H, m), 7.14 (2H, t), 4.04 (2H, t), 3.96 (2H, s),3.67-3.60 (1H, m), {4-[5-Cyclopropyl- 4-(4,7-diaza- spiro[2.5]oct-7-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(2,6- difluoro-phenyl)-amine 3.42 (2H, t), 2.64-2.60 (1H, m), 1.28-1.24 (2H, m), 1.03-1.00 (4H,m), 0.82 (2H, t). 830

method 5: RT: 2.66 min, MI: 493 [M + H] 1H NMR (DMSO, 500 MHz) 9.81 (1H,s), 9.07 (1H, s), 8.43 (1H, d), 8.28 (1H, m), 8.20 (1H, s), 7.97 (1H,m), 4.25 (2H, m), 2.54 (1H, m), 1.23 (3H, m), 1.16 (2H, m), 1.09 (3H,m). {4-[5-Cyclopropyl- 4-((S)-3-methyl- piperazin-1-yl)- pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(3,5,6- trifluoro-pyridin-2- yl)-amine(Piperazine aliphatic protons under the water peak at 3.33 ppm,therefore not integrated). 831

505.27 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(7- cyclopropyl- [1,2,4]triazolo[1,5-a]pyridin-2-yl)- amine 832

456.27 (M + H) {4-[5-Cyclopropyl- 4-(3,3-dimethyl- piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(1- methyl-1H-pyrazol-3-yl)- amine 833

488 (M + H) {5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- methyl-piperidin-4-yl-amine 834

524.26 1-{5-Cyclopropyl-2- [2-(3-morpholin- 4-yl-phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidin-4-ol 835

486.33 ((R)-1-Cyclohexyl- ethyl)-{4-[5- cyclopropyl-4-(3,3-dimethyl-piperazin-1- yl)-pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2-yl}-amine 836

461.18 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(4,6- difluoro-pyridin-2- yl)-amine 837

460 (M + H) {5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- pyrrolidin-3-yl- amine 838

method 5: RT: 3.52 min, MI: 489.41 [M + H] 1H NMR (500 MHz, DMSO, 90°C.) 8.97 (1H, s), 8.90 (1H, s), 8.42 (1H, d), 8.14 (1H, s), 7.97 (1H,dd), 7.81-7.75 (1H, m), 6.67-6.63 (1H, m), 3.81 (2H, s, br), 3.68 (2H,s), 2.95 (2H, s), {4-[5-Cyclopropyl- 4-(3,3-dimethyl- piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(3,6- difluoro-pyridin-2-yl)-amine 1.25 (2H, dd), 0.99-0.96 (8H, m). 839

method 5: RT: 2.39 min, MI: 507 [M + H] 1H NMR (DMSO, 500 MHz) 10.91(1H, s), 9.09 (1H, s), 9.03 (1H, s), 8.78 (1H, s), 8.65 (1H, s), 8.49(1H, d), 8.20 (1H, s), 8.09 (1H, dd), 7.99 (1H, dd), 7.92 (1H, m), 4.34(2H, m), {4-[5-Cyclopropyl- 4-((S)-3-methyl- piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(5- trifluoromethyl-pyridin-2-yl)-amine 3.71 (1H, m), 3.42 (4H, m), 3.06 (1H, m), 1.30 (5H,m), 1.08 (2H, m). 840

method 5: RT: 2.50 min, MI: 471.42 [M + H] 1H NMR (500 MHz, DMSO, 90°C.) 8.97 (2H, s), 8.64 (1H, s, br), 8.39 (1H, d d), 8.15 (1H, dd), 8.13(1H, s), 7.89 (1H, dd), 7.65-7.60 (1H, m), 7.07-7.02 (1H, m), 3.79 (2H,t, br), 3.67 (2H, s), {4-[5-Cyclopropyl- 4-(3,3-dimethyl-piperazin-1-yl)- pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(3-fluoro-pyridin-2-yl)- amine 2.95 (2H, s), 1.25 (2H, dd), 0.99-0.96 (8H,m). 841

method 5: RT: 3.13 min, MI: 481.47 [M + H] 1H NMR (500 MHz, DMSO, 90°C.) 9.08 (1H, s), 8.40 (1H, dd), 8.23 (1H, s), 8.01 (1H, s), 7.85 (1H,s, br), 7.79- 7.78 (5H, m), 3.99-3.97 (4H, m), 3.37-3.35 (4H, m), 2.82(3H, s), 2.72- 2.68 (1H, m), 1.29-1.27 -[4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-ylamino]-N-methyl- benzamide (2H, m), 1.06-1.04 (2H, m). 842

474 (M + H) {5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}- piperidin-3-yl- amine 843

method 5: RT: 2.36 min, MI: 488 [M + H] 1H NMR (DMSO, 400 MHz, 90° C.)9.06 (1H, s), 8.22 (2H, m), 7.74 (1H, s), 7.71 (1H, dd), 7.29 (1H, m),7.13 (2H, t), 4.30 (2H, m), 3.53 (2H, m), 3.21 (2H, {4-[5-Cyclopropyl-4-((3R,5S)-3,5- dimethyl-piperazin- 1-yl)-pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6- difluoro-phenyl)- m), 2.66 (1H, m), 1.33 amine (6H,d), 1.93 (2H, m), 1.04 (2H, m). 844

1H NMR (500 MHz, DMSO) 9.09 (1H, s), 8.83 (1H, d), 8.64 (1H, s), 8.51(1H, d), 8.29 (1H, dd), 8.21 (1H, s), 8.12 (1H, s), 8.07 (1H, d), 7.63(1H, d), 7.54 (1H, s), 3.96 (4H, s, br), 3.34 (4H, s), 2.72-2.676-[4-(5- Cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-ylamino]- nicotinamide (1H, m), 1.27-1.24 (2H, m), 1.09-1.08(2H, m). 845

method 5: RT: 3.87 min, MI: 507.41 [M + H] 1H NMR (500 MH, DMSO) 10.07(1H, s), 9.05 (1H, s), 8.85 (1H, s), 8.47 (1H, d), 8.20 (1H, s), 8.02(1H, d), 7.01 (1H, dd), 3.91 (4H, s, br), 3.35 (2H, s, br), 2.55 (2H, s,br), 1.32- {4-[5-Cyclopropyl- 4-(3,3-dimethyl- piperazin-1-yl)-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(3,4,6-trifluoro-pyridin-2- yl)-amine 1.02 (13H, m). 846

505.25 (MH)+ [4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(8- cyclopropyl- [1,2,4]triazolo[1,5-a]pyridin-2-yl)- amine

General synthesis of substituted substituted2-morpholin-4-yl-pyrido[3,4-d]pyrimidine derivatives of general formula[H-006] Scheme C1

Amino-isonicotinamide derivatives of general formula [H-002] wereprepared by reaction of a substituted amino-isonicotinamide derivativeof general formula [H-001] with di-tert-butyl dicarbonate and ammoniumcarbonate in a polar aprotic solvent such as DMA, DMF, NMP with a basepyridine. Substituted 2-mercapto-3H-pyrido[3,4-d]pyrimidin-4-onederivatives of general formula [H-003] were prepared by cyclisation of aAmino-isonicotinamide derivatives of general formula [H-002] with carbondisulfide in a polar aprotic solvent such as DMA, DMF, NMP with ahindered base such as DBU. 2-Chloro-pyrido[3,4-d]pyrimidin-4-olderivatives of general formula [H-004] were prepared by reaction of aSubstituted 2-mercapto-3H-pyrido[3,4-d]pyrimidin-4-one derivatives ofgeneral formula [H-003] with thiophosgene in a polar aprotic solventsuch as 1,4-dioxane. The 2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-olderivatives of general formula [H-005] were prepared by the reaction ofa 2-Chloro-pyrido[3,4-d]pyrimidin-4-ol derivative of general formula[H-004] with a substituted morpholine derivative of general formula[H-007] in a polar aprotic solvent such as DMA, DMF, NMP at hightemperature either by heating thermally or using a microwave reactor.2-morpholin-4-yl-pyrido[3,4-d]pyrimidine derivatives of general formula[H-006] were prepared by the reaction of a2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-ol derivatives of generalformula [H-005] with 2,4,6-triisopropylbenzenesulfonyl chloride in apolar aprotic solvent such as DMA, DMF, NMP with a tertiary alkylaminebase such as Et₃N, DIPEA or NMM and a catalytic amount of DMAP. Theintermediate 6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-2-morphol-4-yl-pyrido[3,4-d]pyrimidin-4-yl ester was then reactedwith a primary or secondary amino derivative, of general formula[H-008], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, theN-Boc derivatives were deprotected under acidic conditions with a strongacid such as TFA, TCA, methanesulfonic acid, HCl or H₂SO₄ in a solventsuch as DCM, DCE, THF, EtOH or MeOH and the crude reaction product waspurified by reverse phase preparative HPLC.

Synthesis of4-((S)-3-Benzyl-piperazin-1-yl)-2-morpholin-4-yl-pyridol3,4-dlpyrimidine[1000]

3-Amino-isonicotinamide [C001]

A slurry of 3-aminoisonicotinic acid (1.00 g, 7.24 mmol) and CDI (1.76g, 10.85 mmol) in DMF (15 mL) was heated to 40° C. for 0.5 h thencooled. Concentrated aqueous ammonia (50 mL) was added and the mixturewas stirred for 15 min then extracted with ethyl acetate. Removal of thesolvent gave a solid which was dissolved in EtOAc. The organic phase waswashed with water and brine, dried over MgSO₄, filtered and thenconcentrated under reduced pressure to give the title compound[C001](780 mg, 79%) LCMS method: 5, RT: 0.54 min, MI 138 [M+H].

2-Mercapto-3H-pyrido[3,4-d]pyrimidin-4-one hydrochloride [C002]

3-Amino-isonicotinamide [C001](5 g, 36.46 mmol) was dissolved in DMF (40mL). Carbon disulfide (11 mL, 183 mmol) and DBU (10.9 mL, 73 mmol) wereadded and the reaction heated to 60° C. for 2 hours. 2M HCl (40 mL) wasadded and the precipitate was collected, washed with water and driedunder vacuum, to yield the title compound [C002] as a white solid whichwas was used without further purification: LCMS method: 5, RT:1.55 min,MI 180 [M+H].

2-Chloro-3H-pyrido[3,4-d]pyrimidin-4-one hydrochloride [C003]

To a mixture of 2-Mercapto-pyrido[3,4-d]pyrimidin-4-ol [C002](5.45 g,30.41 mmol) in dioxine (100 mL) was added thiophosgene (3.5 mL, 45.6mmol) dropwise and the mixture was heated at 100° C. for 3h. The mixturewas allowed to cool to room temperature and the resulting solid wasdiluted with Et₂O (100 mL) and the precipitate was collected byfitration and the solid was washed with Et₂O to yield the title compoundwhich was used without further purification: LCMS method: 5, RT: 2.61min, MI 182 [M+H].

2-Morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ol [C004]

In a microwave vial, a solution of 2-Chloro-pyrido[3,4-d]pyrimidin-4-olhydrochloride (300 mg, 1.38 mmol) and morpholine (0.22 mL, 2.48 mmol) inDMA (4 mL) was heated under microwave irradiation to 150° C. for 20 min.The solvent was removed under reduced pressure and the resulting solidwas washed with ether and collected to give the title compound [C004]which was used without further purification. LCMS method: 5, RT: 2.20min, MI 232 [M+H].

4-((S)-3-Benzyl-piperazin-1-yl)-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine[1000]

To a solution of 2-Morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ol [C004](100mg, 0.43 mmol) in DMA (3 mL), 2,4,6-Triisopropylbenzenesulfonyl chloride(143 mg, 0.47 mmol), NEt₃ (0.12 mL, 0.86 mmol) and DMAP (10 mg) wereadded successively. The mixture was stirred at rt for 1 h and(S)-1-Boc-2-benzylpiperazine (154 mg, 0.56 mmol) was added. The reactionwas stirred overnight and the solvent was removed under reducedpressure. The mixture was purified by column chromatography on silicagel eluting with CH₂Cl₂ containing 0-10% MeOH. The appropriate fractionswere combined and the solvent removed by rotary evaporation. The residuewas dissolved in CH₂Cl₂ (2 mL) and TFA (0.5 mL) was added. The solutionwas stirred for 3 h and then loaded onto a SCX-2 cartridge, washing withMeOH (6 mL) and eluting with 2 M ammonia in MeOH. The solvent wasremoved from the ammonia fraction to give the title compound [1000]:LCMS method: 5, RT:2.33 min, MI 391 [M+H]; NMR: (1H, 300 MHz, CDCl₃);8.88 (1H, s), 8.10 (1H, d), 7.35-7.21 (7H, m), 4.31-4.21 (2H, m),3.78-3.71 (8H, m), 3.39-3.30 (1H, m), 3.18-3.08 (2H, m), 2.98-2.90 (2H,m), 2.76 (2H, d).

Synthesis of 2-Chloro-5-methoxy-pyrido[3,4-d]pyrimidin-4-olhydrochloride [C-005]

3-amino-5-methoxy-isonicotinamide [C-006]

A stirred suspension of 3-Amino-5-methoxy-isonicotinic acid (1.00 g,5.947 mmol) in anhydrous dioxane (10 mL) was prepared under nitrogen atroom temperature. Pyridine (0.53 mL, 6.542 mmol) was added followed bydi-tert-butyl dicarbonate (1.43 g, 6.542 mmol) and ammonium carbonate(1.26 g, 13.083 mmol). The reaction mixture was stirred at roomtemperature for 5 hours then diluted with diethyl ether (50 mL) and thesuspension stirred at room temperature for 18 hours. The suspension wasfiltered and the solid washed with diethyl ether (50 mL) then dissolvedin methanol and filtered to remove the inorganic salts. The filtrate wasconcentrated by rotary evaporation to give the title compound[C-006](690 mg, 70%) as a cream coloured solid. LCMS method: 5, RT 1.27min, MI 168 [M+H]; NMR: (1H, 300 MHz, d6-dmso) 7.77 (s, 1H), 7.65 (br.S, 1H), 7.58 (br. S, 1H), 7.57 (s, 1H), 6.30 (s, 2H), 3.85 (s, 3H).

2-Mercapto-5-methoxy-3H-pyrido[3,4-d]pyrimidin-4-one [C-007]

A suspension of 3-Amino-5-methoxy-isonicotinamide [C-006](1.10 g, 6.58mmol) in anhydrous DMF (10 mL) was prepared under nitrogen. Carbondisulfide (1.97 mL, 32.90 mmol) was added followed by drop-wise additionof DBU (1.96 mL, 13.16 mmol) and the reaction mixture heated to 60° C.for 2.5 hours. The reaction mixture was cooled to room temperature anddiluted with 2M HCl, the precipitate was filtered and washed with water.The precipitate was suspended in toluene (40 mL), the toluene wasdecanted and this was repeated once more. The precipitate was thensuspended in toluene (30 mL) and concentrated by rotary evaporation toyield the title compound [C-007](1.05 g, 65%) as a yellow solid. LCMSmethod: 5, RT 2.33 min, MI 210 [M+H]; NMR: (1H, 500 MHz, d6-dmso) 12.71(1H, s), 12.38 (1H, s), 8.30 (1H, s), 8.22 (1H, s), 3.95 (3H, s).

2-Chloro-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol hydrochloride [C-005]

A suspension of 2-Mercapto-5-methoxy-3H-pyrido[3,4-d]pyrimidin-4-onehydrochloride [C-007](1.145 g, 4.660 mmol) in anhydrous dioxane (20 mL)was prepared under nitrogen. Thiophosgene (0.54 mL, 6.990 mmol) wasadded drop-wise. The reaction mixture was stirred at room temperaturefor 10 min and then heated to 95° C. for 4 hours. A further portion ofthiophosgene (0.09 mL, 1.165 mmol) was added and heating continued for afurther 1.5 hours before stirring at room temperature overnight. Thereaction mixture was diluted with diethyl ether and the precipitate wasfiltered, washed with diethyl ether and dried under vacuum to give thetitle compound [C-003](1.16 g, 100%) as a pale yellow solid. LCMSmethod: 5, RT 2.71 min, MI 212 [M+H]; NMR: (1H, 500 MHz, d6-dmso) 8.53(1H, s), 8.40 (1H, s), 3.98 (3H, s).

Synthesis of[2-(2-Benzyl-morpholin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine[1001]

2-(2-Benzyl-morpholin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol [C008]

Following the procedure described in Scheme C1,2-Chloro-pyrido[3,4-d]pyrimidin-4-ol hydrochloride (100 mg, 0.459 mmol)was reacted with 2-Benzyl-morpholine (146 mg, 0.825 mmol) to give thetitle compound [C008](114 mg, 64%) following column chromatography onsilica, eluting with CH₂Cl₂ containing 0-10% MeOH. LCMS method: 5, RT2.37 min, MI 323.24 [M+H].

(R)-3-[2-(2-Benzyl-morpholin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester [C009]

To a stirred solution of2-(2-Benzyl-morpholin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol [C008](70 mg,0.21 mmol), NEt₃ (90 mL, 0.63 mmol) and DMAP (3 mg, 0.02 mmol) in DMA (1mL) was added 2,4,6-triisopropylbenzenesulfonyl chloride (77 mg, 0.25mmol). After 4 h (R)-(+)-1-Boc-3-aminopyrrolidine (43 mL, 0.25 mmol) wasadded and stirred overnight at RT. The reaction mixture was partitionedbetween CH₂Cl₂ and H₂O and the organic phase separated and evaporated.The residue was purified by column chromatography on silica, elutingwith CH2Cl2 containing 0-5% MeOH. The appropriate fractions werecombined and evaporated to give the title compound [C009](43 mg, 33%) asan off-white solid. LCMS method: 5, RT 3.59 min, MI 491.33 [M+H].

[2-(2-Benzyl-morpholin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine[1001]

(R)-3-[2-(2-Benzyl-morpholin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester [C009](34 mg, 0.069 mmol) was stirred in 4N HCl indioxane (2 mL) for 1 h. The reaction mixture was diluted with MeOH andloaded onto a SCX-cartridge, washing with MeOH and eluting with ammoniain methanol. The ammonia phase was evaporated to give the title compound[1001](21 mg, 78%). LCMS method: 5, RT 1.97 min, MI 391.21 [M+H]; NMR:(1H, 300 MHz, d4-MeOD) 8.66 (1H, s), 8.14 (1H, dd), 7.83 (1H, ddd),7.35-7.22 (5H, m), 4.66-4.59 (2H, m), 4.50-4.48 (1H, m), 3.98 (1H, dd),3.71-3.55 (2H, m), 3.44-3.41 (1H, m), 3.16-3.07 (2H, m), 2.99-2.91 (1H,m), 2.85-2.74 (3H, m), 2.34-2.13 (3H, m).

General synthesis of substituted substituted2-morpholin-4-yl-pyrido[3,4-d]pyrimidine derivatives of general formula[H-006] Scheme C2

The 2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl derivatives of generalformula [H-009] were prepared by the reaction of a2-Chloro-pyrido[3,4-d]pyrimidin-4-ol derivative of general formula[H-004] with a chlorinatation agent such as phosphorous oxychloride andthen reacted with primary or secondary amino derivative of generalformula [H-008], in a polar aprotic solvent such as DMA, DMF, NMP in thepresence of a tertiary amine base such as Et₃N, DIPEA or NMM at ambienttemperature. After reaction work up, typically by a liquid-liquidextraction or purification by acidic ion exchange catch-release, the2-morpholin-4-yl-pyrido[3,4-d]pyrimidine derivatives of general formula[H-009] were reacted with a substituted morpholine derivative of generalformula [H-007] in a polar aprotic solvent such as DMA, DMF, NMP at hightemperature either by heating thermally or using a microwave reactor.After reaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the N-Boc derivativeswere deprotected under acidic conditions with a strong acid such as TFA,TCA, methanesulfonic acid, HCl or H₂SO₄ in a solvent such as DCM, DCE,THF, EtOH or MeOH and the crude reaction

product was purified by reverse phase preparative HPLC.

Synthesis of(S)—N¹-(5-Methoxy-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine[1002]

(S)-2-Benzyl-4-(2-chloro-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [C010]

A solution of 2-Chloro-5-methoxy-pyrido[3,4-d]pyrimidin-4-ol [C005](1.04g, 4.911 mmol) in DCE (50 mL) was prepared under nitrogen. DIPEA (1.72mL 9.822 mmol) and POCl₃ (0.46 mL, 4.911 mmol) were added and thereaction mixture stirred at room temperature for 2 hours. The reactionmixture was evapourated under reduced pressure and the residue useddirectly in the next step. A solution of2,4-Dichloro-5-methoxy-pyrido[3,4-d]pyrimidine (280 mg of crude residue,1.228 mmol assuming complete conversion) in DCM (15 mL) was preparedunder nitrogen. Triethylamine (0.34 mL, 2.456 mmol) was added followedby (S)-2-Benzyl-piperazine-1-carboxylicacidtert-butylester (170 mg,0.614 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evapourated under reduced pressure andthe residue purified by chromatography on silica, eluting with DCMcontaining 0-10% MeOH to yield the title compound [C-010](110 mg, 19%):LCMS method: 5, RT 2.55 min, MI 263 [M+H]; NMR: (1H, 500 MHz, d6-dmso)8.69 (1H, d, J=3.7 Hz), 8.39 (1H, d, J=3.7 Hz), 4.10 (3H, s), 3.63 (4H,broad s), 3.54 (4H, broad s), 1.47 (9H, s).

(S)—N¹-(5-Methoxy-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine[1002]

A solution of(S)-2-Benzyl-4-(2-chloro-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [CO10](100 mg, 0.213 mmol) in anhydrous DMA (2 mL)was prepared. Morpholine (19 mg, 0.213 mmol) and DIPEA (0.04 mL, 0.213mmol) were added and the mixture heated to 150° C. for 20 min in themicrowave. The reaction mixture was evapourated under reduced pressureand the crude residue was purified by chromatography on silica elutingwith DCM containing 0-10% MeOH. The product was stirred in 4M HCl indioxane at room temperature for 1 hour and the reaction mixture wasevapourated under reduced pressure and loaded onto an SCX cartridge,washing with methanol and eluting with 7N ammonia in methanol. Theammonia eluent was evapourated under reduced pressure to the titlecompound [1001](46 mg, 51%) as a yellow solid: LCMS method: 5, RT 2.51min, MI 421 [M+H]; NMR: (1H, 500 MHz, d6-dmso) 8.34 (1H, s), 7.82 (1H,s), 7.35-7.32 (2H, m), 7.28-7.25 (3H, m), 4.0-3.97 (1H, m), 3.80 (4H,broad s), 3.62-3.61 (8H, broad m), 3.08-3.03 (1H, m), 2.98-2.91 (1H, m),2.76-2.57 (6H, m).

Synthesis of5-Methoxy-2-morpholin-4-yl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine[1003]

4-(2-Chloro-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [C011]

A stirred suspension of 2-Chloro-5-methoxy-pyrido[3,4-d]pyrimidin-4-olhydrochloride [C005](200 mg, 0.806 mmol) in DCE (10 mL) was preparedunder nitrogen. DIPEA (0.31 mL, 1.773 mmol) was added followed bydrop-wise addition of POCl₃ (0.08 mL, 0.887 mmol). The reaction mixturewas stirred at room temperature for 2 hours. A further portion of DIPEA(0.31 mL, 1.773 mmol) and POCL3 (0.08 mL, 0.887 mmol) were added andstirring continued at room temperature for 3 hours. The reaction mixturewas evapourated under reduced pressure and the residue partitionedbetween CH₂Cl₂ (30 mL) and sat. NaHCO₃ (aq) (30 mL). The organic phasewas separated and the aqueous extracted with CH₂Cl₂ (2×10 mL). Thecombined organic portions were dried (phase separator) and evapouratedunder reduced pressure to give a crude residue containing2,4-Dichloro-5-methoxy-pyrido[3,4-d]pyrimidine (assumed 185 mg, 100%)which was used without further purification. A solution containing crude2,4-Dichloro-5-methoxy-pyrido[3,4-d]pyrimidine (assumed 185 mg, 0.806mmol) in CH₂Cl₂ (10 mL) was prepared under nitrogen. Triethylamine (0.17mL, 1.209 mmol) was added followed by piperazine-1-carboxylic acidtert-butyl ester (120 mg, 0.645 mmol) and the reaction mixture stirredat room temperature overnight. The reaction mixture was evapouratedunder reduced pressure and the residue purified by chromatography onsilica eluting with CH₂Cl₂ containing 0-10% MeOH. The appropriatefractions were combined and concentrated to yield the title compound[1003](177 mg, 58%) as a yellow solid. LCMS method: 5, RT 5.44 min, MI380 [M+H]; NMR: (1H, 500 MHz, d6-dmso) 8.65 (s, 1H), 8.34 (s, 1H), 4.06(s, 3H), 3.59 (br. m, 4H), 3.49 (br. m, 4H), 1.42 (s, 9H).

5-Methoxy-2-morpholin-4-yl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine[C012]

To a solution of 2,4-Dichloro-5-methoxy-pyrido[3,4-d]pyrimidine[C011](70 mg, 0.19 mmol) in DMA (2 mL) was added morpholine (20 mg,0.228 mmol) and DIPEA (0.04 mL, 0.228 mmol). The reaction mixture washeated to 150° C. for 20 min in a microwave. The reaction mixture wasconcentrated under reduced pressure and the crude residue was purifiedby chromatography on silica (eluting with CH2C12 containing 0-10% MeOH)to give the title compound [C012] LCMS method: 5, RT 4.01 min, MI 431[M+H].

5-Methoxy-2-morpholin-4-yl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine[1003]

5-Methoxy-2-morpholin-4-yl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine[C012] was stirred in 4M HCl in dioxane (2 mL) at room temperature for 2hours. The reaction mixture was diluted with methanol (to dissolvedprecipitate) and loaded onto a SCX cartridge, washing with methanol andeluting with 7M ammonia in methanol. The ammonia fraction wasevapourated under reduced pressure and dried under vacuum to give thetitle compound [1003](48 mg, 83%): LCMS method: 5, RT 3.54 min, MI 331[M+H]; NMR: (1H, 500 MHz, d6-dmso) 8.33 (1H, broad d, J=0.9 Hz), 7.88(1H, s), 3.95 (3H, s), 3.73-3.71 (4H, m), 3.64-3.62 (4H, m), 3.38 (4H,broad m), 2.82-2.80 (4H, broad t, J=4.5 Hz).

The following intermediate compounds were synthesised according to thegeneral synthesis shown in scheme [C2]

Analysis Int SM Amine LCMS NMR Name [C013]

Method 5: RT: 522 min, MI: 350 [M + H] 4-(2-Chloro-5- methoxy-pyrido[3,4- d]pyrimidin-4-yl)- piperazine-1- carboxylic acid tert-butylester [C014]

Method 5: RT: 6.18 min, MI: 470 [M + H] (S)-2-Benzyl-4- (2-chloro-4-methoxy- pyrido[3,4- d]pyrimidin-4-yl)- piperazine-1- carboxylic acidtert-butyl ester [C015]

Method 5: RT: 2.99 min, MI: 386 [M + H] (1H, 500 MHz, CDCl₃): 8.82 (1H,s), 8.18 (1H, s), 7.31-7.28 (2H, m), 6.98 (1H, t, J = 7.4), 6.90 (2H, d,J = 7.9 Hz), 4.27- 4.24 (1H, br. d, J = 12.1 Hz), 4.15-4.10 (1H, m),4.06 (3H, 2-Chloro-5- methoxy-4-((R)- 3-phenoxymethyl- piperazin-1-yl)-pyrido[3,4- d]pyrimidine s), 4.03-4.00 (1H, m), 3.98-3.94 (1H, m),3.39-3.34 (1H, br. s), 3.27-3.18 (2H, m), 3.11-3.02 (2H, m). [C016]

Method 5: RT: 5.40 min, MI: 370 [M + H] (1H, 500 MHz, d6- dmso): 8.61(1H, s), 8.29 (1H, s), 7.06 (2H, t, J = 7.6 Hz), 6.77 (1H, br. d, J =7.3 Hz), 6.51 (1H, t, J = 7.3 Hz), 5.61 (1H, d, J = 7.2 Hz), 4.48 (1H,br. s), 4.03 [(S)-1-(2-Chloro- 5-methoxy- pyrido[3,4- d]pyrimidin-4-yl)-piperidin-3-yl]- phenyl-amine (3H, s), 3.85 (1H, br, d, J = 12.7 Hz),3.46-3.40 (1H, br. m), 3.55-3.30 (1H, br. m), 2.83 (1H, t, J = 10.7 Hz),1.99 (1H, br. s), 1.79- 1.78 (1H, br. m), 1.57-1.49 (2H, br. m). [C017]

Method 5: RT: 3.00 min, MI: 404 [M + H] (1H, 500 MHz, d6- dmso) 8.62(1H, s), 8.32 (1H, s), 7.21-7.16 (2H, m), 7.11 (1H, t, J = 7.9 Hz),6.96- 6.93 (1H, m), 4.15- 4.13 (1H, br. m), 4.05-3.97 (3H, m), 4.02 (3H,s), 3.19- 2-Chloro-4-[(R)- 3-(2-fluoro- phenoxymethyl)-piperazin-1-yl]-5- methoxy- pyrido[3,4- d]pyrimidine 3.18 (1H, br. m),3.12-3.03 (2H, m), 2.99-2.95 (1H, m), 2.84-2.79 (1H, br. m). [C018]

Method 5: RT: 3.13 min, MI: 404 [M + H] (1H, 500 MHz, d6- dmso) 8.63(1H, s), 8.34 (1H, s), 7.14-7.10 (2H, m), 6.98-6.95 (2H, m), 4.16-4.12(1H, br m), 4.04 (3H, s), 4.04-3.99 (1H, br m), 3.93 (2H, d), 3.16-3.09(3H, m), 2.98-2.94 (1H, m), 2.84-2.79 2-Chloro-4-[(R)- 3-(4-fluoro-phenoxymethyl)- piperazin-1-yl]-5- methoxy- pyrido[3,4- d]pyrimidine(1H, m). [C019]

Method 5: RT: 5.45 min, MI: 423 [M + H] (1H, 500 MHz, d6- dmso) 8.64(1H, s), 8.34 (1H, s), 4.26 (1H, br. s), 4.20 (1H, br. d, J = 13.2 Hz),4.06 (3H, s), 3.92 (1H, br. d, J = 8 Hz), 3.82- 3.80 (1H, br. m),3.39-3.35 (1H, br. m), 3.31-3.24 (2H, m), 3.21-3.19 (2H,(R)-4-(2-Chloro- 5-methoxy- pyrido[3, 4-d]pyrimidin-4- yl)-2-methoxymethyl- piperazine-1- carboxylic acid tert-butyl ester m), 3.10(3H, br. s), 1.40 (9H, s). [C020]

Method 5: RT: 4.89 min, MI: 410 [M + H] (1H, 500 MHz, d6- dmso) 1.40 (s,9H), 3.17 (t, 1H), 3.22-3.33 (m, 1H), 3.33-3.39 (m, 2H), 3.72-3.82 (m,1H), 3.87-3.92 (m, 1H), 4.05n (s, 3H), 4.02-4.10 (m, 1H), 4.18-4.24 (m,1H), 4.76-4.78 (m, 1H), 8.33 (s, 1H), (R)-4-(2-Chloro- 5-methoxy-pyrido[3, 4-d]pyrimidin-4- yl)-2- hydroxymethyl- piperazine-1-carboxylic acid tert-butyl ester 8.63 (s, 1H). [C021]

Method 5: RT: 4.10 min, MI: 350 [M + H] (2-Chloro-5- methoxy-pyrido[3,4-d]py- rimidin-4-yl)-(R)- pyrrolidin-3-yl- amine

The following compounds were synthesised according to the generalsynthesis shown in scheme [C2]

Analysis Ex Precursor Amine LCMS NMR Name 1004

Method 5: RT: 2.74 min, MI: 437 [M + H] (1H, 500 MHz, d6- dmso) 8.39(1H, s), 7.94 (1H, s), 7.36-7.32 (2H, m), 7.03-6.97 (3H, m), 4.70 (1H,broad, d, J = 12.8 Hz), 4.53 (1H, broad d, J = 13.1 Hz), 4.16-4.10 (2H,m), 4.04-4.00 (1H, m), 4.00 (3H, s), 3.86-3.81 (1H, m), 3.63-3.57 (1H,m), 3.44-3.43 (4H, broad m), 3.20 (1H, d, J = 6 Hz), 3.11- 3.06+ (1H,m), 2.99- 2.94 (1H, m), 2.86 (4H, 5-Methoxy-2-(2- phenoxymethyl-morpholin-4-yl)- 4-piperazin-1- yl-pyrido[3,4- d]pyrimidine broad t, J =4.7 Hz) 1005

Method 5: RT: 3.49 min, MI: 3.61 (M + H] (1H, 500 MHz, d6- dmso) 8.34(1H, s), 7.90 (1H, s), 4.66 (1H, br t, J = 5.1 Hz), 3.98-3.94 (1H, m),3.95 (3H, s), 3.86 (1H, br d, J = 11.8 Hz), 3.74-3.73 (4H, m), 3.66-3.44(4H, m), 3.40-3.33 (2H, m), 2.97-2.88 (2H, m), 2.81-2.75 (2H, m),2.62-2.57 (1H, m). [(R)-4-(5- Methoxy-2- morpholin-4-yl- pyrido[3,4-d]pyrimidin-4- yl)-piperazin-2- yl]-methanol 1006

Method 5: RT: 5.02 min, MI: 4.37 [M + H] (1H, 500 MHz, d6- dmso) 8.34(1H, s), 7.90 (1H, s), 7.30-7.27 (2H, m), 6.94-6.93 (3H, m), 4.90 (1H,br. d, J = 11.9 Hz), 3.96-3.90 (2H, m), 3.94 (3H, s), 3.84 (1H, br. d, J= 11.8 Hz), 3.72-3.70 (4H, m), 3.63-3.61 (4H, m), 3.19 (1H, br. s),3.02- 2.98 (2H, br. m), 2.81- 2.74 (2H, br. m). 5-Methoxy-2-morpholin-4-yl- 4-((R)-3- phenoxymethyl- piperazin-1-yl)- pyrido[3,4-d]pyrimidine 1007

Method 5: RT: 3.12 min, MI: 421 [M + H] (1H, 500 MHz, CDCl₃) 8.54 (1H,s), 7.83 (1H, s), 7.17-7.14 (2H, m), 6.69 (1H, br. t, J = 7.3 Hz), 6.62(2H, br. d, J = 7.5 Hz), 4.02-3.97 (1H, br. m), 4.00 (3H, s), 3.87-3.86(4H, m), 3.77-3.75 (4H, m), 3.69 (1H, br. s), 3.59- 3.55 (1H, br. m),3.36- 3.27 (2H, br. m), 2.04- 1.97 (1H, br. m), 1.89- 1.84 (1H, br. m),1.71- [(S)-1-(5- Methoxy-2- morpholine-4-yl- pyrido[3,4- d[pyrimidin-4-yl)-piperidin-3- yl]-phenyl- amine 1.65 (2H, br. m). 1008

Method 5: RT: 2.54 min, MI: 455 [M + H] (1H, 500 MHz, d6- dmso): 8.33(1H, s), 7.89 (1H, s), 7.22-7.16 (2H, m), 7.11 (1H, br. t, J = 7.5 Hz),6.96-6.92 (1H, m), 4.14 (1H, br. d, J = 12.3 Hz), 4.05-4.02 (1H, m),3.97-3.93 (1H, m), 3.93 (3H, s), 3.83-3.80 (1H, m), 3.72-3.70 (4H, m),3.63-3.61 (4H, m), 3.20 (1H, br. s), 3.03- 2.96 (2H, m), 2.78- 2.73 (2H,m). 4-[(R)-3-(2- Fluoro- phenxoymethyl)- piperazin-1-yl]- 5-methoxy-2-morpholin-4-yl- pyrido[3,4- d]pyrimidine 1009

Method 5: RT: 1.26 min, MI: 375 [M + H] (1H, 500 MHz, d6- dmso): 8.34(1H, s), 7.90 (1H, s), 3.95 (3H, s), 3.91 (1H, br. d, J = 12.4 Hz), 3.84(1H, br. d, J = 12.5 Hz), 3.74-3.72 (4H, m), 3.66-3.64 (4H, m), 3.28(2H, d, J = 5.9 Hz), 3.26 (3H, s), 2.98-2.93 (3H, m), 2.78-2.74 (1H, m),2.66-2.61 (1H, m). 5-Methoxy-4- ((R)-3- methoxymethyl- piperazin-1-yl)-2-morpholin-4- yl-pyrido[3,4- d]pyrimidine 1010

Method 5: RT: 2.62 min, MI: 455 [M + H] (1H, 500 MHz, d6- dmso): 8.35(1H, s), 7.91 (1H, s), 7.14-7.10 (2H, m), 6.97-6.95 (2H, m), 4.07 (1H,br. d, J = 12.2 Hz), 3.95 (3H, s), 3.92- 3.90 (2H, m), 3.84 (1H, br. d,J = 12.2 Hz), 3.73- 3.71 (4H, m), 3.64- 3.62 (4H, m), 3.17- 3.16 (1H,br. m), 3.01- 2.97 (2H, br. m), 2.80- 2.73 (2H, br. m). 4-[(R)-3-(4-Fluoro- phenoxymethyl)- piperazin-1-yl]- 5-methoxy-2- morpholin-4-yl-pyrido[3,4- d]pyrimidine 1011

Method 5: RT: 0.54 min, MI: 301 [M + H] 1H NMR (CDCl₃, 500 MHz) 8.83 (s,1H), 8.19 (d, 1H), 7.49 (d, 1H), 6.74 (d, 1H), 4.85- 4.75 (m, 1H),3.92-3.87 (m, 4H), 3.80-3.75 (m, 4H), 3.31-3.06 (m, 4H), 2.38-2.22 (m,2H). (2-Morpholin-4- yl-pyrido[3,4- d]pyrimidin-4- yl)-(R)-pyrrolidin-3-yl- amine

Synthesis of[2-Morpholin-4-yl-8-(2H-pyrazol-3-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine[1012]

2,8-Dichloro-pyrido[3,4-d]pyrimidin-4-ol [C022]

To a suspension of 3-Amino-2-chloro-isonicotinamide (2.00 g, 11.65 mmol)in dioxane (30 mL), thiophosgene (2.25 mL, 29.13 mmol) was addeddropwise and the suspension was stirred 15 min. The reaction was thenheated at 100° C. for 3 h then cooled down to room temperature anddiluted with Et₂O. The resulting solid was collected and dried to givethe title compound [C022](2.41 g, 96%) which was used without furtherpurification. LCMS method: 5, RT 3.51 min, MI 216 [M+H].

8-Chloro-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ol [C023]

To a solution of 2,8-Dichloro-pyrido[3,4-d]pyrimidin-4-ol [C022](200 mg,0.926 mmol) in DMA (2 mL), morpholine (0.1 mL, 1.20 mmol) was added. Thesolution was stirred at room temperature for 30 min then heated to 40°C. for 3 h. The solvent was removed under reduced pressure, a minimumamount of CH₂Cl₂ was added to dissolve the crude residue and Et₂O wasadded. The resulting solid was collected and dried to give the titlecompound [C022](200 mg, 80%) which was used without furtherpurification. LCMS method: 5, RT 3.95 min, MI 267 [M+H].

(R)-3-(8-Chloro-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylicacid tert-butyl ester [C024]

To a solution of 8-Chloro-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ol[C022](500 mg, 1.87 mmol) in DMA (10 mL),2,4,6-Triisopropylbenzenesulfonyl chloride (690 mg, 2.25 mmol), NEt₃(0.52 mL, 3.75 mmol) and DMAP (50 mg, 0.41 mmol) were addedsuccessively. The mixture was stirred at 40° C. for 1 h and then(R)-3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (460 mg, 2.44mmol). The reaction was stirred overnight at room temperature then thesolvent was removed under reduced pressure. The mixture was purified bycolumn chromatography on silica eluting with CH₂Cl₂ containing 0-10%MeOH. The appropriate fractions were combined and evapourated underreduced pressure to give the title compound [C023](310 mg, 38%). LCMSmethod: 5, RT 5.77 min, MI 435 [M+H].

[2-Morpholin-4-yl-8-(2H-pyrazol-3-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine[1012]

A microwave vial was charged with(R)-3-(8-Chloro-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylicacid tert-butyl ester [C024](100 mg, 0.23 mmol), 1H-Pyrazole-5-boronicacid (38 mg, 0.35 mmol), Pd(Ph₃P)₄ (27 mg, 0.023 mmol), a solution ofK₃PO₄ (0.92 mL of a 0.5M in H₂O, 0.46 mmol) and DMA (3.5 mL). Themixture was heated under microwave irradiation to 150° C. for 10 min.The solvent was removed under reduced pressure and the residue purifiedby chromatography on silica, eluting with CH₂Cl₂ containing 0-10% MeOH.The appropriate fractions were combined and the solvent evaporated underreduced pressure to give the Boc-protected intermediate which wasdissolved in CH₂Cl₂ (2 mL) and TFA (0.5 mL) was added. The solution wasstirred for 3 h and then loaded onto a SCX-2 cartridge, washing withMeOH and eluting with 2N ammonia in MeOH solution. The solvent wasremoved from the ammonia fraction under reduced pressure to yield thetitle compound [1012]: LCMS method: 5, RT 4.39 min, MI 367 [M+H]; NMR:(1H, 300 MHz, d6-dmso) 8.28 (d, 1H), 7.96 (d, 1H), 7.60 (d, 1H), 7.33(d, 1H), 4.61-4.68 (m, 1H), 3.78-3.81 (m, 4H), 3.68-3.74 (m, 4H),3.33-3.40 (m, 2H), 3.18-3.23 (m, 1H), 3.02-3.07 (m, 1H), 2.15-2.24 (m,1H), 1.98-2.04 (m, 1H).

Synthesis ofN⁴—((S)-2-Amino-3-phenyl-propyl)-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine-4,8-diamine[1013]

[(S)-1-Benzyl-2-(8-chloro-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [C025]

Following the procedure described above,8-Chloro-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-o [C023]1 (500 mg,1.87 mmol) was reacted with ((S)-1-Aminomethyl-2-phenyl-ethyl)-carbamicacid tert-butyl ester (600 mg, 2.44 mmol) to give the title compound[C024](350 mg, 38%). LCMS method: 5, RT 5.90 min, MI 499 [M+H].

N⁴—((S)-2-Amino-3-phenyl-propyl)-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine-4,8-diamine

A microwave vial was charged with[(S)-1-Benzyl-2-(8-chloro-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-carbamicacid tert-butyl ester [C025](100 mg, 0.20 mmol), EtOH (2 mL) and NH₄OH(2 mL). The reaction mixture was heated under microwave irradiation to150° C. for 1 h. This was repeated until reasonable conversion to thedesired product was identified by LCMS analysis. The solvent was thenremoved under reduced pressure and the BOC protected compounds werediluted in CH₂Cl₂ (2 mL) and TFA (0.5 mL) was added. The solution wasstirred for 3 h and then loaded onto a SCX-2 cartridge, washing withMeOH and eluting with 2M ammonia in MeOH solution. The solvent wasremoved from the ammonia fraction and the residue was purified bypreparative HPLC (method A) to yield the title compound [1013] LCMSmethod: 5, RT 2.11 min, MI 380 [M+H]; NMR: (1H, 300 MHz, d6-dmso)8.30-8.35 (m, 1H), 8.27 (br s, 1H), 7.49 (d, 1H), 7.22-7.33 (m, 4H),6.97 (d, 1H), 6.34 (br s, 2H), 3.68-3.78 (m, 1H), 3.61-3.65 (m, 1H),3.37-3.54 (m, 8H), 3.25-3.35 (m, 2H), 2.91 (dd, 1H), 2.73 (dd, 1H).

Synthesis of(S)—N¹-(2-Morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine[1014]

2-Chloro-pyrido[3,4-d]pyrimidin-4-ol [C003](1.50 g, 8.26 mmol) wassuspended in DMA (30 mL). Triethylamine (2.3 mL, 16.52 mmol) was addedand the reaction mixture stirred at room temperature.2,4,6-Triisopropylbenzenesulfonyl chloride (2.75 g, 9.09 mmol) and DMAP(50 mg, 0.41 mmol) were both added and the mixture was stirred at roomtemperature for 6 hours. ((S)-1-Aminomethyl-2-phenyl-ethyl)-carbamicacid tert-butyl ester (3.10 g, 12.39 mmol) was added to the reactionmixture and stirring continued at room temperature for 18 hours. To thecrude solution was added morpholine (1 mL) and the mixture sealed andheated under microwave irradiation to 150° C. for 20 min. The mixturewas taken up in DCM and washed with water and brine. The layers wereseparated and the organic layer was dried over MgSO₄. The solvent wasremoved under reduced pressure and the crude mixture purified by flashcolumn chromatography; eluting with a 5% methanol in CH₂Cl₂. Theappropriate fractions were combined and concentrated and the residuestirred in 4M HCl in dioxane for 18 hours. The mixture was concentratedunder reduced pressure and the residue loaded onto a SCX cartridge,washing with MeOH and eluting with 2M ammonia in methanol. The solventwas removed from the ammonia fraction under reduced pressure to give thetitle compound [1014](150 mg, 22%). LCMS method: 5, RT 1.79 min, MI 365[M+H]; NMR: (1H, 300 MHz, d6-dmso) 8.73 (1H, br s), 8.64 (1H, s), 8.29(2H, br s), 8.20 (1H, d), 8.00 (1H, d), 7.38-7.28 (5H, m), 3.90-3.83(1H, m), 3.62-3.34 (10H overlapping br m), 3.13-3.07 (1H, m), 2.88-2.81(1H, m).

General synthesis of substituted substituted2-morpholin-4-yl-pyrido[3,4-d]pyrimidine derivatives of general formula[H-006] Scheme C3

3-halo-N-(imino-morpholin-4-yl-methyl)-isonicotinamide derivatives ofgeneral formula [H-011] were prepared by coupling of aortho-halo-isonicotinic acid derivative of general formula [H-010] withan appropriately substituted 4-carbamimidoyl-morpholine of generalformula [H-004] with a suitable coupling agent such asO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in a polar aprotic solvent such as DMA orDMF. The isonicotinoyl-amidine derivative of general formula [H-011]were cyclised to displace the relevant halogen group to yield thedesired morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives ofgeneral formula [H-005]. The2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl derivatives of generalformula [H-006] were prepared by the reaction of amorpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ol derivatives of generalformula [H-005] with a chlorinatation agent such as phosphorousoxychloride or a triflating agent such asN-Phenyl-bis(trifluoromethanesulfonimide and then reacted with primaryor secondary amino derivative of general formula [H-008], in a polaraprotic solvent such as DMA, DMF, NMP in the presence of a tertiaryamine base such as Et₃N, DIPEA or NMM at ambient temperature. Afterreaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the N-Boc derivativeswere deprotected under acidic conditions with a strong acid such as TFA,TCA, methanesulfonic acid, HCl or H₂SO₄ in a solvent such as DCM, DCE,THF, EtOH or MeOH and the crude reaction product was purified by reversephase preparative HPLC.

Synthesis of5-Bromo-2-morpholin-4-yl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine[1015]

3-Bromo-5-fluoro-N-(imino-morpholin-4-yl-methyl)-isonicotinamide [C026]

A stirred solution of 3-Bromo-5-fluoro-isonicotinic acid hydrochloride(800 mg, 3.119 mmol) and DIPEA (1.91 mL, 10.917 mmol) in DMF (11 mL) wasprepared. HATU (1.186 g, 3.119 mmol) was added and the reaction mixturestirred at room temperature for 1 hour, during which time reactionmixture turned slowly brown. 4-Morpholinylformamidine hydrobromide (655mg, 3.119 mmol) was added and stirring continued at room temperature for2 hours. The reactionmixture was diluted with water (30 mL) and stirredat room temperature for 10 mins. The reaction mixture was extracted withEtOAc (3×20 mL) and the combined organics dried and evapoutrated underreduced pressure to give the title compound [C026] a brown gum (1.15 g,87%) which was used without purification in the next step: LCMS method:5, RT 2.86 min, MI 331 [M+H].

5-Bromo-2-morpholin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [C027]

A solution of3-Bromo-5-fluoro-N-(imino-morpholin-4-yl-methyl)-isonicotinamide[C025](crude product containing 1.03 g, 3.119 mmol starting materialassuming 100% conversion) in anhydrous DMA (10 mL) was prepared andpotassium carbonate (453 mg, 3.275 mmol) was added. The reaction mixturewas heated to 150° C. for 1 hour in the microwave. The reaction mixturewas poured into water (20 mL) and acidified with acetic acid. Theresulting beige precipitate was filtered, washed with water and dried inthe vac. oven over night to give the title compound [C027](400 mg, 41%):LCMS method: 5, RT 1.42 min, MI 313 [M+H].

5-Bromo-2-morpholin-4-yl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine[1015]

A solution of 5-Bromo-2-morpholin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one(50 mg, 0.161 mmol) in anhydrous DMF (2 mL) was prepared under nitrogen.N-Phenyl-bis(trifluoromethanesulfonimide) (60 mg, 0.169 mmol) was addedfollowed by DIPEA (0.06 mL, 0.354 mmol) and the reaction mixture stirredat room overnight. Piperazine-1-carboxylic acid tert-butyl ester (60 mg,0.322 mmol) was added and stirring continued at room temperatureovernight. The reaction mixture was concentrated under reduced pressureand the residue diluted with EtOAc (10 mL) and washed with water (3×5mL). The organic phase was dried, filtered and concentrated by rotaryevaporation. The residue was purified by chromatography on silica,eluting with cyclohexane containing 5-50% EtOAc. The appropriatefractions were combined and concentrated to give4-(5-Bromo-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [C027](35 mg, 45%) as a yellow solid. LCMS method:5, RT 5.92 min, MI 479 [M+H]; NMR: (1H, 500 MHz, d6-dmso) 8.67 (1H, s),8.29 (1H, s), 3.78-3.76 (4H, m), 3.66-3.62 (4H, m), 3.62 (2H, very broads), 3.52-3.47 (4H, very broad m), 3.24 (2H, very broad s), 1.40 (9H, s).

The Boc protected intermediate [C026] was taken up in 4M HCl in dioxane(2 mL) and stirred at room temperature 2 hours. The reaction mixture wasconcentrated by rotary evaporation and the residue loaded onto a SCX-2cartridge, washing with MeOH and eluting with 7N ammonia in MeOH. Theammonia fraction was concentrated under reduced pressure to give thetitle compound [1015](24 mg, 86%) as a yellow solid. LCMS method: 5, RT2.24 min, MI 379 [M+H]; NMR: (1H, 500 MHz, CDCl₃) 8.76 (1H, s), 8.28 (s,1H), 3.89-3.87 (4H, m), 3.78-3.76 (4H, m), 3.70 (2H, br. s), 3.33 (2H,br. s), 3.09 (2H, br. s), 3.00 (2H, br. s).

Synthesis of5-Cyclopropyl-2-morpholin-4-yl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine

A solution of4-(5-Bromo-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [C028](110 mg, 0.229 mmol) in anhydrous dioxane(2.5 mL) was prepared in a microwave vial. potassium phosphate(tribasic) (ground, 145 mg, 0.687 mmol) and cyclopropyl boronic acid (30mg, 0.344 mmol) were added. The reaction mixture was purged with argon(vacuum/argon balloon) 3 times and thenDichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (9 mg, 0.011 mmol) was added and the vial sealedand heated to 95° C. for 5 hours. The reaction mixture was cooled toroom temperature and allowed to stand overnight. The reaction mixturewas evaporated onto silica and purified by chromatography on silica,eluting with CH₂Cl₂ containing 0-8% MeOH. The product was not purifiedwith this solvent system and so the appropriate fractions wereconcentrated and purification repeated, eluting with cyclo-hexanecontaining 50-100% EtOAc. The appropriate fractions were combined andconcentrated to give4-(5-Cyclopropyl-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester (53 mg, 52%) as a yellow glassy solid. LCMSmethod: 5, RT 4.09 min, MI 441 [M+H]; NMR: (1H, 500 MHz, d6-dmso) 8.50(1H, s), 7.68 (1H, s), 3.79-3.19 (8H, very broad set of signals),3.79-3.74 (4H, m), 3.66-3.64 (4H, m), 2.62-2.59 (1H, m), 1.40 (9H, s),1.18-1.14 (2H, m), 0.93-0.90 (2H, m). The Boc-protected intermediate wasstirred in 4M HCl in dioxane (2 mL) at room temperature for 2 hours. Thereaction mixture was concentrated by rotary evaporation and loaded ontoa SCX cartridge, washing with MeOH and eluting with 7N ammonia in MeOH.The ammonia fraction was concentrated by rotary evaporation to give thetitle compound [1016](37 mg, 90%) as a pale yellow solid. LCMS method:5, RT 4.41 min, MI 341 [M+H]; NMR: (1H, 500 MHz, d6-dmso) 8.48 (1H, s),7.65 (1H, s), 3.75-3.73 (4H, m), 3.66-3.62 (overlapping 4H m and 2H verybroad s), 3.19 (2H, very broad s), 2.80 (4H, br. m), 2.63-2.58 (1H, m),1.17-1.14 (2H, m), 0.93-0.90 (2H, m).

Synthesis of4-((S)-3-Benzyl-piperazin-1-yl)-5-cyclopropyl-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine[1017]

(S)-2-Benzyl-4-(5-bromo-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [C029]

Following the procedure described in ScemeC3,5-Bromo-2-morpholin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [C027](200mg, 0.64 mmol) was reacted with(S)-2-Benzyl-piperazine-1-carboxylicacidtert-butylester (355 mg, 1.28mmol) to give(S)-2-Benzyl-4-(5-bromo-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [C028](139 mg, 38%). LCMS method: 5, RT: 5.64 min,MI: 569/571 [M+1].

4-((S)-3-Benzyl-piperazin-1-yl)-5-cyclopropyl-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine

Following the procedure described in Scheme C3,(S)-2-Benzyl-4-(5-bromo-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [C029](135 mg, 0.24 mmol) was reacted withcyclopropyl boronic acid (31 mg, 0.36 mmol) to give4-((S)-3-Benzyl-piperazin-1-yl)-5-cyclopropyl-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine[1017](62mg, 61%)s a yellow solid. LCMS method: 5, RT 2.74 min, MI 431 [M+H];NMR: (1H, 500 MHz, CDCl₃) 8.66 (1H, s), 7.65 (1H, s), 7.33-7.19 (5H, m),4.35-2.42 (18H, very broad overlapping multiplets), 1.16-1.08 (2H, brm), 0.90-0.82 (2H, br m).

Synthesis of[(S)-4-(5-Cyclopropyl-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazin-2-yl]-acetonitrile[1018]

3-Cyclopropyl-5-fluoro-N-(imino-morpholin-4-yl-methyl)-isonicotinamide[C030]

Following the procedure described in Scheme C3, trifluoro-acetate4-carboxy-3-cyclopropyl-5-fluoro-pyridinium (1.51 g, 5.10 mmol) wasreacted with 4-Morpholinylformamidine hydrobromide (1.56 g, 5.10 mmol)to give3-Cyclopropyl-5-fluoro-N-(imino-morpholin-4-yl-methyl)-isonicotinamide[C029](1.23 g, 84%) which was used without purification in the nextstep.

LCMS method: 5, RT 2.35 min, MI 293 [M+H].

Step 2: 5-Cyclopropyl-2-morpholin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[C031]

Following the procedure described in SchemeC3,3-Cyclopropyl-5-fluoro-N-(imino-morpholin-4-yl-methyl)-isonicotinamide(1.26 g, 4.30 mmol) was treated with K₂CO₃ under microwave irradiationto 5-Cyclopropyl-2-morpholin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one[C030](402 mg, 34%). LCMS method: 5, RT 3.41 min, MI 273 [M+H].

[(S)-4-(5-Cyclopropyl-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazin-2-yl]-acetonitrile[1018]

A stirred solution of5-Cyclopropyl-2-morpholin-4-yl-3H-pyrido[3,4-d]pyrimidin-4-one [C031](50mg, 0.184 mmol) in DMF (5 mL) was prepared at room temperature undernitrogen. Triethylamine (0.03 mL, 0.193 mmol) was added followed by2,4,6-triisopropylbenzenesulfonyl chloride (56 mg, 0.186 mmol). Thereaction mixture was stirred at room temperature for 2 hours then(S)-Piperazin-2-yl-acetonitrile (23 mg, 0.184 mmol) was added. Thereaction mixture was stirred at room temperature overnight. The reactionmixture was concentrated under reduced pressure and the residue purifiedby chromatography on silica, eluting with CH₂Cl₂ containing 0-10% MeOH.The appropriate fractions were combined and concentrated to give thetitle compound [1018](30 mg, 43%) as a yellow solid. LCMS method: 5, RT5.76 min, MI 380 [M+H]; NMR: (1H, 500 MHz, CDCl₃) 8.69 (1H, s), 7.70(1H, s), 4.46-4.29 (1H, br s), 3.95-3.93 (1H, br m), 3.88 (4H, t), 3.78(4H, t), 3.32-3.27 (1H, m), 3.20-2.66 (5H, br m), 2.50 (2H, br s), 1.80(1H, br s), 1.16 (2H, br s), 0.95 (2H, br s).

4PPAZ Compounds

Several methods for the chemical synthesis of4-substituted-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-azaquinazoline compounds(for convenience, collectively referred to herein as “4PPAZ compounds”)of the present application are described herein, of general formula[I-001]. These and/or other well known methods may be modified and/oradapted in known ways in order to facilitate the synthesis of additionalcompounds within the scope of the present application.

General synthesis of substituted substituted4-substituted-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-azaquinazolinederivatives of general formula [I-001] Scheme D1

The 4-substituted-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-azaquinazolinederivatives of general formula [1-003] were prepared by the reaction ofa 2-Chloro-pyrido[3,4-d]pyrimidine derivative of general formula[I-002], prepared in scheme C2, in a Suzuki type palladium catalysedcross coupling reaction with boronic acid or boronate ester derivativeof general formula [I-004] a palladium catalyst such as Pd(PPh₃)₄, abase such as K₂PO₄ in a polar aprotic solvent such as DMA or DMF atelavated temperature either by heating thermally or using a microwavereactor, to yield 4PPAZ derivative of general formula [I-003]. Afterreaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the intermediate waspurified by column chromatography. The intermediate arylsulphonateprotected derivative of general formula [I-003] was then subjected to adeprotection reaction in the presence of a base such as sodium hydroxidein a polar protic solvent such as ethanol. After reaction work up,typically by a liquid-liquid extraction or purification by acidic ionexchange catch-release, the intermediate was purified by columnchromatography and the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, HCl in a solvent such as DCM,DCE or 1,4-dioxane or by catch and release sulfonic acidic resins suchas polymer supported toluene sulfonic acid and the crude reactionproduct was purified by normal phase chromatography or reverse phasepreparative HPLC.

Synthesis of5-Methoxy-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine[1200][011] [D001]

4-{5-Methoxy-2-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperazine-1-carboxylicacid tert-butyl ester [D001]

A solution of4-(2-Chloro-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylicacid tert-butyl ester [C011 prepared in scheme C2](250 mg, 0.671 mmol)in DMA (7.5 mL) was prepared.4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine[D002](374 mg, 0.940 mmol), Pd(PPh₃)₄(77 mg, 0.067 mmol) and K₃PO₄ (2.68mL of a 0.5 M solution in water) were added. The reaction mixture washeated to 150° C. in the microwave for 10 min. The reaction mixture wasconcentrated by rotovap and purified by column chromatography on silica,eluting with cyclohexane containing 0-100% EtOAc. The appropriatefractions were combined and concentrated to give the title compound[D001]](115 mg, 28%) as a yellow solid. LCMS method: 5, RT 5.13 min, MI616 [M+H]; NMR: (1H, 500 MHz, d6-dmso) 8.92 (s, 1H), 8.53 (d, 1H), 8.37(s, 1H), 8.26 (d, 1H), 8.05 (d, 1H), 8.02 (d, 1H), 7.77 (d, 1H),7.64-7.60 (m, 1H), 7.57-7.53 (m, 1H), 7.43 (d, 2H), 4.09 (s, 3H), 3.67(br. m, 4H), 3.56 (br. m, 4H), 1.43 (s, 9H).

5-Methoxy-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine

A solution of4-{5-Methoxy-2-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperazine-1-carboxylicacid tert-butyl ester [D001](100 mg, 0.162 mmol) in ethanol (4 mL) wasprepared and NaOH (1 mL of a 5 M solution) was added. The reactionmixture was stirred at room temperature overnight. The reaction mixturewas concentrated by rotary evaporation and the residue dissolved in DCM(10 mL) and water (10 mL). The pH was adjusted to approx 7 by additionof ammonium chloride and the mixture extracted with DCM (3×10 mL). Thecombined organic extracts were dried (phase separator) and concentratedby rotary evaporation. The residue was purified by column chromatographyon silica, eluting with cyclohexane containing 75-100% EtOAc. Theappropriate fractions were combined and concentrated to giveintermediate4-[5-Methoxy-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester which was stirred in 4M HCl in dioxane (2 mL) atroom temperature for 1 hour. The reaction mixture was concentrated byrotary evaporation, loaded onto a SCX cartridge, washed with methanoland eluted with 7N ammonia in methanol. The ammonia fraction wasconcentrated by rotary evaporation to give the title compound [1200](29mg, 49%) as a yellow solid. LCMS method: 5, RT 2.23 min, MI 362 [M+H];NMR: (1H, 500 MHz, d6-dmso) 11.81 (1H, s), 8.89 (1H, s), 8.37 (1H, d,J=5.0 Hz), 8.31 (1H, s), 8.09 (1H, d, J=5.0 Hz), 7.63-7.62 (1H, m), 7.43(1H, dd, J=3.3, 1.8 Hz), 4.07 (3H, s), 3.66-3.64 (4H, m), 2.91-2.89 (4H,m).

General synthesis of substituted boronic acid or boronate esterderivative of general formula [I-004] Scheme D2

The substituted boronic acid or boronate ester derivatives of generalformula [I-004] were prepared by the reaction of a4-Bromo-1H-pyrrolo[2,3-b]pyridine derivative of general formula [I-005]with an arylsuphonyl chloride derivative of general formula [I-008] witha base such as NaH in a polar aprotic solvent such as THF at lowtemperature. The 1-arylsulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridinederivative of general formula [I-006] was then reacted with a strongbase such as LDA, in a polar aprotic solvent such as THF at lowtemperature and a alkyl halide derivative of general formula [I-009].The C2 substituted 4-bromo-1H-pyrrolo[2,3-b]pyridine derivative ofgeneral formula [I-007] was then reacted in a palladium catalysed crosscoupling reaction with a palladium catalyst such as PdCl₂ dppf, a boronagent such as bispinocolatodiboron, potassium acetate in a polar aproticsolvent such as dioxane at elavated temperature either by heatingthermally or using a microwave reactor, to yield the substitutedboronate ester derivative of general formula [I-004] which afterreaction work up, typically by a liquid-liquid extraction was purifiedby column chromatography.

Synthesis of4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine[D002]

4-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [D003]

4-Bromo-7-azaindole (3 g, 15.22 mmol) was weighed into a round bottomflask and dissolved in THF (50 mL) under nitrogen. The reaction mixturewas cooled to 0° C. and treated portionwise with sodium hydride (60% inmineral oil, 0.67 g, 16.75 mmol), the addition was accompanied byfizzing. After the addition the reaction mixture was allowed to stir for30 minutes at room temperature and then treated with benzenesulfonylchloride (2.14 mL, 16.75 mmol). The reaction mixture was allowed to warmto room temperature and stirred for 2 hours. The reaction mixture wasevaporated under reduced pressure and dissolved in DCM 30 mL, theorganics were washed with 2×30 mL portions of 2M sodium carbonate, driedwith MgSO4, filtered and evaporated to an orange oil. Purified by flashcolumn chromatography eluting with 1:9 ethyl acetate:cyclohexane toprovide the title compound as an off white solid (92%). LCMS method: 5,RT 5.36 min, MI 337 [M+H]; NMR: (1H, 500 MHz, CDCl₃) 8.22 (d, 1H), 8.18(d, 2H), 7.78 (d, 1H), 7.58 (t, 1H), 7.48 (t, 2H), 7.35 (d, 1H), 6.63(d, 1H).

4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine[D002]

4-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.57 g, 4.47mmol), Bis(pinacolato)diboron [D003](2.71 g, 10.72 mmol), PdCl2.dppfCH2C12 adduct (0.365 g, 0.45 mmol) and potassium acetate (0.876 g, 8.94mmol) were weighed into a microwave vial. Dioxane (30 mL) was added andthe reaction mixture was capped and heated at 130 OC in a microwavereactor for 30 minutes. The solvent was removed under reduced pressureand the residue was partitioned between ammonium chloride 20 mL andethyl acetate 20 mL. The organics were dried with MgSO4, filtered andevaporated under reduced pressure to a brown oil. This was passedthrough a short column of silica eluting with 1:4 ethylacetate:cyclohexane. The fractions were pooled and evaporated to yieldthe title compound [D002] as a pale yellow solid: LCMS method: 5, RT4.77 min, MI 317 [M+H for boronic acid intermediate]

Synthesis ofBenzenesulfonyl-2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine[D004]

1-Benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridine [D005]

4-Bromo-7-azaindole (3 g, 15.22 mmol) was weighed into a round bottomflask and dissolved in THF (50 mL) under nitrogen. The reaction mixturewas cooled to 0° C. and treated portionwise with sodium hydride (60% inmineral oil, 0.67 g, 16.75 mmol), the addition was accompanied byfizzing. After the addition the reaction mixture was allowed to stir for30 minutes at room temperature and then treated with benzenesulfonylchloride (2.14 mL, 16.75 mmol). The reaction mixture was allowed to warmto room temperature and stirred for 2 hours. The reaction mixture wasevaporated under reduced pressure and dissolved in DCM 30 mL, theorganics were washed with 2×30 mL portions of 2M sodium carbonate, driedwith MgSO4, filtered and evaporated to an orange oil. Purified by flashcolumn chromatography eluting with 1:9 ethyl acetate: cyclohexane toprovide the title compound [D005] as an off white solid (92%): LCMSmethod: 5, RT 5.36 min, MI 337 [M+H]; NMR: (1H, 500 MHz, CDCl₃) 8.22 (d,1H), 8.18 (d, 2H), 7.78 (d, 1H), 7.58 (t, 1H), 7.48 (t, 2H), 7.35 (d,1H), 6.63 (d, 1H).

1-Benzenesulfonyl-4-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine [D006]

To a solution of 1-Benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridine[D005](2 g, 5.93 mmol) in THF (50 mL) at −78° C., LDA (2M, 5.9 mL, 11.86mmol) was added dropwise. The solution was stirred 30 min. Thetemperature was allowed to warm to 0° C. and Methyl iodide (3.67 mL, 59mmol) was then added dropwise and the solution was stirred 3h at 0° C.and was allowed to stir to room temperature overnight. The reaction wasquenched with aqueous ammonium chloride solution and extracted with DCM.The combined organic layers were dried over MgSO4 and concentrated invacuo. The crude was purified by SP1 (eluent, gradiant:Cyclohexane/AcOEt: 1/0 to 8/2). The fractions were collected andconcentrated under reduced pressure to yield the title compound [D006] awhite solid (87%). LCMS method: 5, RT 5.80 min, MI 351 [M+H]; NMR: (1H,500 MHz, CDCl₃) 8.12-8.15 (m, 3H), 7.56 (t, 1H), 7.47 (t, 2H), 7.29 (d,1H), 6.34 (s, 1H), 2.74 (s, 3H).

Benzenesulfonyl-2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine[D004]

Following the procedure described in schenme D2 replacing1-Benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridine with1-Benzenesulfonyl-4-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine gave thetitle compound [D004](72%%) as a pale yellow solid. LCMS method: 5, RT6.19 min, MI 399 [M+H]; NMR: (1H, 500 MHz, CDCl₃) 8.34 (d, 1H), 8.07 (d,2H), 7.50 (t, 1H), 7.46 (d, 1H), 7.41 (t, 2H), 6.70 (s, 1H), 2.73 (s,3H), 1.33 (s, 12H).

The following compounds were prepared according to Scheme D2:

1-Benzenesulfonyl-2-benzyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine[D007]

1-Benzenesulfonyl-2-benzyl-4-bromo-1H-pyrrolo[2,3-b]pyridine [D008]

Following the procedure described in schemeD2,1-Benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridine was reacted withbenzyl bromide to give the title compound [D008] which was used crude inthe next step. LCMS method: 5, RT 6.62 min, MI 427 [M+H].

1-Benzenesulfonyl-2-benzyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine[D007]

Following the procedure described in scheme D2 replacing1-Benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridine with1-Benzenesulfonyl-2-benzyl-4-bromo-1H-pyrrolo[2,3-b]pyridine gave thetitle compound [D007] as a pale yellow solid: LCMS method: 5, RT 5.59min, MI 392 [M+H, Boronic ester hydrolysed into the correspondingboronic acid in the LCMS conditions]; NMR: (1H, 500 MHz, d6-dmso) 8.38(d, 1H), 7.70 (dd, 1H), 7.49 (d, 1H), 7.42 (t, 1H), 7.23-7.30 (m, 7H),6.75 (s, 1H), 4.54 (d, 2H), 1.34 (s, 12H).

Synthesis of1-Benzenesulfonyl-2-(2-fluoro-benzyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine[D009]

Step 1:1-Benzenesulfonyl-4-bromo-2-(2-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine[D010]

Following the procedure described in schemeD2,1-Benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridine was reacted with2-fluorobenzylbromide to give the title compound [D010](75%): LCMSmethod: 5, RT 6.45 min, MI 445 [M+H].

Step 2:1-Benzenesulfonyl-2-(2-fluoro-benzyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine[D009]

Following the procedure described in scheme D2 replacing1-Benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridine with1-Benzenesulfonyl-4-bromo-2-(2-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridinegave the title compound [D009] as a white solid. LCMS method: 5, RT 5.50min, MI 411 [M+1, hydrolysed boronic ester to its corresponding boronicacid].

Synthesis of1-Benzenesulfonyl-2-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine[D011]

1-Benzenesulfonyl-4-bromo-2-ethyl-1H-pyrrolo[2,3-b]pyridine [D012]

Following the procedure described in schemeD2,1-Benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridine was reacted withiodoethane to give the title compound [D012] as a white solid: LCMSmethod: 5, RT 6.01 min, MI 351 [M+H]; NMR: (1H, 500 MHz, d6-dmso)8.11-8.15 (m, 3H), 7.56 (d, 1H), 7.45-7.48 (m, 2H), 7.30 (d, 1H), 6.39(s, 1H), 3.19 (q, 2H), 1.42 (t, 3H).

1-Benzenesulfonyl-2-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine[D011]

Following the procedure described in schemeD 2 replacing1-Benzenesulfonyl-4-bromo-1H-pyrrolo[2,3-b]pyridine with1-Benzenesulfonyl-4-bromo-2-ethyl-1H-pyrrolo[2,3-b]pyridine gave thetitle compound [D011] as a pale yellow solid. LCMS method: 5, RT 6.42min, MI 413 [M+H]; LCMS Method 1LCMS5, 6.42 min, MI: 413 [M+1].

The following compounds were synthesised according to the generalsynthesis shown in scheme [D1]

Analysis Ex Precursor Boronic ester LCMS NMR Name 1201

Method 5: RT: 2.39 min, MI: 376 [M + H] (1H, 500 MHz, d6- dmso) 3.44(brs, 4H), 3.86- (brs, 4H), 4.10 (s, 3H), 7.16 (s, 1H), 8.06 (d, 1H),8.25 (d, 1H), 8.39 (s, 1H), 8.92 (brs, 2H), 8.98 (s, 1H), 11.77 (brs,1H). 5-Methoxy-2- (2-methyl-1H- pyrrolo[2,3- b]pyridin-4- yl)-4-piperazin-1-yl- pyrido[3,4- d]pyrimidine 1202

Method 5: RT: 3.49 min, MI: 452 [M + H] (1H, 500 MHz, d6- dmso)3.19-3.39 (m, 3H), +H2O), 3.77-3.83 (m, 4H), 4.08 (s, 3H), 4.16 (s, 2H),7.08 (s, 1H), 7.24 (t, 1H), 7.32-7.40 (m, 4H), 8.05 (d, 1H), 8.26 (d,1H), 8.36 (s, 1H), 8.90 (s, 1H), 8.97 (brs, 2H), 11.86 (s, 1H).2-(2-Benzyl- 1H- pyrrolo[2,3- b]pyridin-4- yl)-5-methoxy- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidine 1203

Method 5: RT: 3.39 min, MI: 470 [M + H] (1H, 500 MHz, d6- dmso) 2.96(brs, 4H), 3.60 (brs, 4H), 4.05 (s, 3H), 4.18 (s, 2H), 6.96 (s, 1H),7.19-7.23 (m, 2H), 7.32-7.44 (m, 2H), 8.03 (s, 1H), 8.27 (d, 1H), 8.29(s, 1H), 8.79 (s, 1H), 11.87 (brs, 1H). 2-[2-(2- Fluoro- benzyl)-1H-pyrrolo[2,3- b]pyridin-4- yl]-5-methoxy- 4-piperazin-1- yl-pyrido[3,4-d]pyrimidine 1204

2-(2-Ethyl-1H- pyrrolo[2,3- b]pyridin-4- yl)-5methoxy- 4-piperazin-1-yl-pyrido[3,4- d]pyrimidine 1205

Method 5: RT: 2.53 min, MI: 406 [M + H] 5-Methoxy-4- ((R)-3-methoxymethyl- piperazin-1- yl)-2-(1H- pyrrolo[2,3- b]pyridin-4-yl)-pyrido[3,4- d]pyrimidine 1206

Method 5: RT: 2.36 min, MI: 392 [M + H] (1H, 500 MHz, d6- dmso)2.86-2.96 (m, 3H), 3.10 (d, 1H), 3.15-3.19 (m, 1H), 3.39-3.45 (m, 2H),4.06 (s, 3H), 4.15- 4.24 (m, 2H), 7.43-7.44 (m, 1H), 7.60-7.61 (m, 1H),8.08 (d, 1H), 8.19 (s, 1H), 8.32 (s, 1H), 8.35 (d, 1H), 8.89 (s, 1H),11.89 (brs, 1H). {(R)-4-[5- Methoxy-2- (1H- pyrrolo[2,3- b]pyridin-4-yl)-pyrido[3,4- d]pyrimidin-4- yl]piperazin- 2-yl}- methanol 1207

Method 5: RT: 1.99 min, MI: 332 [M + H] (1H, 500 MHz, d6- dmso)2.94-2.97 (m, 4H), 3.89-3.93 (m, 4H), 7.45 (t, 1H), 7.63 (t, 1H), 7.90(d, 1H), 8.11 (d, 1H), 8.37 (d, 1H), 8.57 (d, 1H), 9.32 (s, 1H), 11.83(brs, 1H). 4-Piperazin-1- yl-2-(1H- pyrrolo[2,3- b]pyridin-4-yl)-pyrido[3,4- d]pyrimidine 1208

Method 5: RT: 1.91 min, MI: 332 [M + H] (1H, 500 MHz, d6- dmso)2.21-2.28 (m, 1H), 2.34-2.44 (m, 1H), 3.33-3.50 (m, 3H), 3.67-3.74 (m,2H), 4.95-5.04 (m, 1H), 7.50 (d, 1H), 7.63 (t, 1H), 8.15 (d, 1H), 8.25(d, 1H), 8.38 (d, 1H), 8.64 (d, 1H), 8.70 (d, 1H), 9.30 (s, 1H), 11.86(s, 1H) (R)-Pyrrolidin- 3-yl-[2-(1H- pyrrolo[2,3- b]pyridin-4-yl)-pyrido[3,4- d]pyrimidin-4- yl]-amine

General synthesis of substituted substituted4-substituted-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-azaquinazolinederivatives of general formula [I-001] Scheme D3

The 4-substituted-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-azaquinazolinederivatives of general formula [I-001] were prepared by the reaction ofa halogenated pyridine derivative of general formula [I-010] with astrong base such as LDA, in a polar aprotic solovent such as THF, asymmetrical anhydride such as Di-tert-butyl dicarbonate at lowtemeperature to yield halo-substituted-isonicotinic acid tert-butlyester derivatives of general formula [I-011]. After reaction work up,typically by a liquid-liquid extraction the intermediate was purified bycolumn chromatography. The halo-substituted-isonicotinic acid tert-butlyester derivative of general formula [I-011] was then subjected to aSuzuki type palladium catalysed cross coupling reaction with boronicacid or boronate ester derivative of general formula [I-018] a palladiumcatalyst such as Pd(PPh₃)₄, a base such as K₂PO₄ in a polar aproticsolvent such as DMA or DMF at elavated temperature either by heatingthermally or using a microwave reactor, to yield thesubstituted-isonicotinic acid tert-butly ester derivative of generalformula [I-012]. After reaction work up, typically by a liquid-liquidextraction the intermediate was purified by column chromatography. Thet-butylester inter intermediate[1-012] was then subjected to adeprotection reaction in the presence of a base such as sodium hydroxidein a polar protic solvent such as ethanol to yield thesubstituted-isonicotinic acid derivative of general formula [I-013],which was then subjected to a coupling reaction with a substituted1H-pyrrolo[2,3-b]pyridine-4-carboxamidine derivative of general formula[I-014], with a suitable coupling agent such asO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in a polar aprotic solvent such as DMA orDMF. The isonicotinoyl-amidine derivative of general formula [I-015] canthen be cyclised to displace the relevant halogen group to yield thedesired 2-(1H-pyrrolo[2,3-b]pyridine-4-yl)-pyrido[3,4-d]pyrimidin-4-olderivative of general formula [I-016]. The4-substituted-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-azaquinazolinederivatives of general formula [I-001] were prepared by the reaction ofa 2-(1H-pyrrolo[2,3-b]pyridine-4-yl)-pyrido[3,4-d]pyrimidin-4-olderivative of general formula [I-016] with a chlorinatation agent suchas phosphorous oxychloride to give compounds of general formula and theintermediate 4-chloro derivative was then further reacted with primaryor secondary amino derivative of general formula [I-017], in a polaraprotic solvent such as DMA, DMF, NMP in the presence of a tertiaryamine base such as Et₃N, DIPEA or NMM at ambient temperature [method A].After reaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release, the N-Boc derivativeswere deprotected under acidic conditions with a strong acid such as TFA,TCA, methanesulfonic acid, HCl or H₂SO₄ in a solvent such as DCM, DCE,THF, EtOH or MeOH and the crude reaction product was purified by normalphase silica gel chromatography or reverse phase preparative HPLC.4-substituted-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-azaquinazolinederivatives of general formula [I-001] were prepared by the reaction ofa -(1H-pyrrolo[2,3-b]pyridine-4-yl)-pyrido[3,4-d]pyrimidin-4-olderivative of general formula [I-016] with2,4,6-triisopropylbenzenesulfonyl chloride in a polar aprotic solventsuch as DMA, DMF, NMP with a tertiary alkylamine base such as Et₃N,DIPEA or NMM and a catalytic amount of DMAP [method B]. The intermediate6,7-substituted-(2,4,6-triisopropyl-benzenesulfonicacid)-(1H-pyrrolo[2,3-b]pyridine-4-yl)-pyrido[3,4-d]pyrimidin-4-yl esterwas then reacted with a primary or secondary amino derivative, ofgeneral formula [G-117], in a polar aprotic solvent such as DMA, DMF,NMP in the presence of a tertiary amine base such as Et₃N, DIPEA or NMMat ambient temperature. After reaction work up, typically by aliquid-liquid extraction or purification by acidic ion exchangecatch-release, the N-Boc derivatives were deprotected under acidicconditions with a strong acid such as TFA, TCA, methanesulfonic acid,HCl or H₂SO₄ in a solvent such as DCM, DCE, THF, EtOH or MeOH and thecrude reaction product was purified by reverse phase preparative HPLC.

Synthesis of5-Cyclopropyl-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine[1209]

3-Bromo-5-fluoro-isonicotinic acid tert-butyl ester [D013]

To a solution of LDA (2M, 72 mL, 144 mmol) in THF (100 mL) at −78° C.was added dropwise via cannula a solution of 3-bromo-5-fluoropyridine(21.12 g, 120 mmol) in THF (50 mL) pre-cooled at −78° C. During theaddition the internal temperature did not rise above−65° C. The darkred-brown solution was stirred for 1 hour. Di-tert-butyldicarbonate(52.4 g, 240 mmol) in THF (50 mL) was cooled to −10° C. in amethanol/ice bath then added dropwise via cannula to the dark red-brownsolution. The mixture was stirred for 2 hours then allowed to warm toroom temperature and stir for 1 hour. Saturated aqueous ammoniumchloride (100 mL) was added slowly and then water (200 mL) and EtOAc(200 mL) and the mixture was vigorously stirred for 45 minutes. Themixture was transferred to a separatory funnel and the layers wereseparated. The aqueous layer was extracted with EtOAc (200 mL). The THFand EtOAc layers were combined, dried over magnesium sulfate, filteredand evaporated. The recovered dark red-brown oil was purified by columnchromatography (Cyclohexane/AcOEt: 1/0 to 97/3). Fractions containingdesired material were concentrated in vacuo (14 g, 85%). LCMS method: 5,RT 5.44 min, MI 277 [M+H]; NMR: (1H, 500 MHz, CDCl3) 8.56 (s, 1H), 8.43(s, 1H), 1.62 (s, 9H).

3-Cyclopropyl-5-fluoro-isonicotinic acid tert-butyl ester [D014]

A solution containing 3-Bromo-5-fluoro-isonicotinic acid tert-butylester [D013](5.52 g, 20 mmol), potassium phosphate tribasic (12.74 g, 60mmol) and cyclopropyl boronic acid (2.58 g, 30 mmol), in dioxane (100mL) was subjected to vacuum/argon balloon (three times).Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.408 g, 0.5 mmol) was added and the reactionheated at 96° C. overnight under positive pressure of nitrogen. Themixture was cooled to room temperature and was filtered through a pad of200 g silica and washed with EtOAc (1 L). The filtrate was concentratedin vacuo and the crude was purified by column chromatography(Cyclohexane/AcOEt: 98:2 to 96:4). The combined fractions wereconcentrated under reduced pressure to give the title compound [D014] asa colourless oil (3.42 g, 72%). LCMS method: 5, RT 5.36 min, MI 238[M+H]; NMR: (1H, 500 MHz, CDCl3) 8.33 (s, 1H), 8.15 (s, 1H), 2.05-2.00(m, 1H), 1.62 (s, 9H), 1.04-1.00 9m, 2H), 0.82-0.78 (m, 2H).

3-Cyclopropyl-5-fluoro-isonicotinic acid [D015]

In a microwave vial, 3-cyclopropyl-5-fluoro-isonicotinic acid tert-butylester [D014](1.186 g, 5 mmol) was dissolved in methanol and then heatedin microwave at 140° C. for 1 hr. The reaction was concentrated in vacuoto yield the title compound [D015] 0.84 g (92%) of white crystallinesolid. LC-MS: 1NJM406_1_28Jul2011; 1.51 min, 87%; 182+; 1LCMS5.

3-Cyclopropyl-5-fluoro-N-[imino-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-isonicotinamide[D016]

3-Cyclopropyl-5-fluoro-isonicotinic acid [D015](0.681 g, 3.76 mmol),HATU (1.43 g, 3.76 mmol) and diisopropyethylamine (2.29 mL, 13.16 mmol)were stirred in DMF (5 mL). After 1 hr,1H-Pyrrolo[2,3-b]pyridine-4-carboxamidine; acetic acid salt (0.92 g,3.76 mmol) was added. Having stirred for 18 hr the mixture was pouredinto water (180 ml), stirred for 2 hours and then a white solidcollected by filtration and washed with H₂O to yield the title compound[D016] as a white solid (1.17 g) was used without further purification.LCMS method: 5, RT 3.22 min, MI 324 [M+H].

5-Cyclopropyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ol [D017]

A mixture ofN-[(2-Chloro-pyridin-4-yl)-imino-methyl]-3-cyclopropyl-5-fluoro-isonicotinamide[D016](1.164 g, 3.6 mmol) and Cs2CO3 (1.18 g, 3.60 mmol) in DMA (12 mL)was heated thermally at 90° C. overnight. The reaction mixture waspoured into H₂O (20 ml) and acidified with dropwise addition of aceticacid at 0 OC. The beige precipitate (0.474, 43%) was collected byfiltration and washed with H₂O to yield the title compound [D017] whichwas used without further purification. LCMS method: 5, RT 4.58 min, MI304 [M+H]; NMR: (1H, 500 MHz, d6-dmso) 12.12 (brs, 1H), 9.09 (s, 1H),8.54 (d, 1H), 8.37 (s, 1H), 7.90 (d, 1H), 7.83 (s, 1H), 7.36 (s, 1H),3.56-3.64 (m, 1H), 1.24-1.30 (m, 2H), 1.08-1.14 (m, 2H).

4-[5-Cyclopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [D018]

To a solution of 5-Cyclopropyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-o[D017]1 (0.47 g, 1.55 mmol) in DMF (25 mL) was added DIPEA (0.809 mL,4.65 mmol) and DMAP (5 mg). 2,4,6-Triisopropylbenzenesulfonyl chloride(0.563 g, 1.86 mmol) was then added and the mixture was stirred 2 hours.N-Boc-Piperazine (0.318 g, 1.705 mmol) was then added and the mixturewas the stirred overnight. Water was added water (60-70 mL) and thesolution was stirred at RT for 15 mins. The resulting solid wascollected and washed twice with water. The solid was dissolved in DCMand purified by column chromatography (eluent: DCM/MeOH gradient 0% to10% MeOH) to yield the title compound [D018] as a dark brown gum (0.6 g,82%) was used without further purification in the next step. LCMSmethod: 5, RT 5.85 min, MI 472 [M+H].

5-Cyclopropyl-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine

To a solution of4-[5-Cyclopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [D018](0.6 g, 1.27 mmol) in DCM (15 mL) was addedHCl (4N, dioxane, 2 mL) and the resultant bright yellow suspension wasstirred at RT for 90 mins. The solution was concentrated under reducedpressure and dissolved in MeOH and added to SCX-2 cartridge (10 g),washed with MeOH/DCM (1:1, 40 mL) and MeOH (20 mL). Then the SCX-2cartridge was washed with ammonia (7N in MeOH, 30 mL). The ammoniawashes were concentrated in vacuo and the material purified on thecolumn chromatography (eluent DCM/MeOH gradient 0-20% MeOH/DCM). Thefractions were combined and concentrated under reduced pressure to yieldthe title compound [1009]: LCMS method: 5, RT 2.65 min, MI 372 [M+H];NMR: (1H, 500 MHz, d6-dmso) 11.82 (brs, 1H), 9.13 (s, 1H), 8.36 (d, 1H),8.10 (d, 1H), 7.62 (t, 1H), 7.45 (dd, 1H), 3.50-3.90 (m, 4H), 2.88-2.91(m, 4H), 2.66-2.69 (m, 1H), 1.22-1.27 (m, 2H), 1.02-1.06

Synthesis of8-Chloro-5-cyclopropyl-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine[1210]

5-Bromo-2-chloro-3-fluoro-isonicotinic acid tert-butyl ester [D019]

Following the procedure described in scheme D31,5-Bromo-2-chloro-3-fluoro-isonicotinic acid tert-butyl ester wasprepared [D019] as acolourless oil by reaction of5-bromo-2-chloro-3-fluoropyridine, LDA (2M), Di-tert-butyldicarbonate,and THF. LCMS method: 5, RT 6.25 min, MI 311 [M+H].

S2-Chloro-5-cyclopropyl-3-fluoro-isonicotinic acid tert-butyl ester[D020]

Following the procedure decribed in schemeD3,5-Bromo-2-chloro-3-fluoro-isonicotinic acid tert-butyl ester wasreacted with cyclopropyl boronic acid to give2-Chloro-5-cyclopropyl-3-fluoro-isonicotinic acid tert-butyl ester[D020]. LCMS method: 5, RT 6.19 min, MI 272 [M+H].2-Chloro-5-cyclopropyl-3-fluoro-isonicotinic acid[D021]2-Chloro-5-cyclopropyl-3-fluoro-isonicotinic acid tert-butyl ester[D020](815 mg, 3.00 mmol) was suspended in 2-propanol (9 mL) and HCl (5mL of a 4M solution in dioxane) was added. The reaction mixture washeated to 50° C. overnight. The reaction mixture was concentrated underreduced pressure to the title compound [D021](530 mg, 82%) as a whitecrystalline solid which was used without purification. LCMS method: 5,RT 0.91 min, MI 216 [M+H].

2-Chloro-5-cyclopropyl-3-fluoro-N-[imino-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-isonicotinamide[D022]

Following the procedure described in schemeD3,2-chloro-5-cyclopropyl-3-fluoro-isonicotinic acid [D021] was reactedwith 1H-Pyrrolo[2,3-b]pyridine-4-carboxamidine to give the titlecompound [D022]. LCMS method: 5, RT 4.45 min, MI 358 [M+H].

8-Chloro-5-cyclopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol[D023]

Following the procedure described in schemeD3,2-Chloro-5-cyclopropyl-3-fluoro-N-[imino-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-isonicotinamide[D022] was reacted with Cs₂CO₃ to give the title compound [D023]. LCMSmethod: 5, RT 4.87 min, MI 306 [M+H].

4-[8-Chloro-5-cyclopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [D024]

Following the procedure described in schemeD3,8-Chloro-5-cyclopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol[D023] was reacted with 1-Boc-piperazine to give the title compound[D024]. LCMS method: 5, RT 6.05 min, MI 506 [M+H].

8-Chloro-5-cyclopropyl-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine[1210]

Following the procedure described in scheme D3, 84-[8-Chloro-5-cyclopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [D024] was reacted with 4N HCl in dioxane to givethe title compound [1210]: LCMS method: 5, RT 3.22 min, MI 406 [M+H].

Synthesis of-Isopropyl-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine[1211]

3-Fluoro-5-isopropenyl-isonicotinic acid tert-butyl ester [D025]

Following the procedure described schemeD3,3-Bromo-5-fluoro-isonicotinic acid tert-butyl ester [D013] wasreacted with isopropenylboronic acid pinacol ester (containsphenothiazine as stabilizer), withdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct as catalyst to give3-Fluoro-5-isopropenyl-isonicotinic acid tert-butyl ester [D025]. LCMSmethod: 5, RT 5.41 min, MI 238 [M+H].

3-Fluoro-5-isopropyl-isonicotinic acid tert-butyl ester [D026]

To a solution of 3-Fluoro-5-isopropenyl-isonicotinic acid tert-butylester [D025] in EtOH was added ammonium formate and palladium oncharcoal (5% wt/wt) and the mixture was heated at 60° C. overnight. Moreammonium formate was added and the mixture was stirred for a further 45min at 60° C. then was allowed to cool down to room temperature and wasstirred overnight. The mixture was filtered through a celite pad andwashed with EtOAc. Water was added to the filtrate and the layers wereseparated. The organic was dried over MgSO4 and concentrated in vacuo.The crude was purified by column chromatography (gradiantCyclohexane/AcOEt: 1:0 to 92:8). The combined fractions wereconcentrated under reduced pressure to led the title compound [D026] asa pale yellow oil (0.34 g, 37%). LCMS method: 5, RT 5.55 min, MI 240[M+H]; NMR: (1H, 500 MHz, CDCl3) 8.42 (1H, s), 8.35 (1H, s), 3.09 (1H,sept), 1.60 (9H, s), 1.33 (6H, d).

3-Fluoro-5-isopropyl-isonicotinic acid [D027]

To a solution of 3-Fluoro-5-isopropyl-isonicotinic acid tert-butyl ester[D026](0.335 g, 1.4 mmol) in isopropyl alcohol (5 mL), a solution of HCl(4N in dioxane, 1 mL) was added and the solution was warmed to 50° C.overnight. LC-MS implies some progress but not complete. HCl (4N indioxane, 1 mL) was added again and left at 50° C. overnight. Thereaction is still not complete so more HCl (4N in dioxane, 1 mL) wasadded and left through the day (˜6-7 hrs). The solution was concentratedin vacuo to yield the title compound [D027] an off-white solid which wasused without further purification and analysis.

3-Fluoro-N-[imino-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-5-isopropyl-isonicotinamide[D028]

Following the procedure described in schemeD3,3-Fluoro-5-isopropyl-isonicotinic acid was reacted [D027] with,1H-Pyrrolo[2,3-b]pyridine-4-carboxamidine togive3-Fluoro-N-[imino-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-5-isopropyl-isonicotinamide[D028]. LCMS method: 5, RT 3.67 min, MI 326 [M+H].

5-Isopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol[D029]

Following the procedure described in scheme D3,3-Fluoro-N-[imino-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-5-isopropyl-isonicotinamide[D028] was treated with Cs₂CO₃ to give5-Isopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol[D029] as a brown solid. LCMS method: 5, RT 4.87 min, MI 306 [M+H].

4-[5-Isopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [D030]

Following the procedure described in scheme D3,5-Isopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol[D029] was treated with 1-Boc-piperazine to give the title compound[D030] as a brown solid. LCMS method: 5, RT 5.78 min, MI 474 [M+H].

5-Isopropyl-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine

Following the procedure described in scheme D3,4-[5-Isopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester [D030] was treated with 4N HCl to give the titlecompound[1211] as a brown solid. LCMS method: 5, RT 2.82 min, MI 374[M+H], NMR: (1H, 500 MHz, CDCl3) 9.28 (1H, s), 9.0 (1H, br s), 8.61 (1H,s), 8.46 (1H, s), 8.23 (1H, d), 7.63 (1H, s), 7.47 (1H, s), 4.07 (1H,m), 3.86 (2H, m), 3.49 (2H, m), 3.11 (4H, m), 1.25 (6H, d).

General synthesis of substituted1H-pyrrolo[2,3-b]pyridine-4-carboxamidine derivative of general formula[I-012] Scheme D4

The substituted 1H-pyrrolo[2,3-b]pyridine-4-carboxamidine derivatives ofgeneral formula [I-012] were prepared by the reaction of 2-methylpyridine-2-yl carbamic acid tert butyl ester derivative of generalformula [I-019] with a strong base such as nBuLi, in a polar aproticsolovent such as THF, and a substituted Weinreb amide derivative ofgeneral formula [I-025] at low temeperature followed by reaction with amineral acid such as hydrochloric acid at elevated temperature to yieldthe 1-H-pyrrolo[2,3-b]pyridine derivative of general formula [I-020],after reaction work up, typically by a liquid-liquid extraction theintermediate was purified by column chromatography. The1-H-pyrrolo[2,3-b]pyridine derivative of general formula [I-020] wasthen subjected to a pyridine N-oxidation reaction with an oxidisingreagent such as mCPBA in a solvent such as DCM. The intermediate1-H-pyrrolo[2,3-b]pyridine-7-oxide derivative of general formula [I-021]was then reacted with a chlorinating agent such as methansulfonylchloride, in a polar aprotic solvent such as DMF at elevatedtemperature, after reaction work up, typically by a liquid-liquidextraction the intermediate was purified by column chromatography. Theintermediate 4-chloro-1H-pyrrolo[2,3-b]pyridine derivative of generalformula [I-022] was then submitted to a palladium catalysed crosscoupling reaction with a cyanide species such as zinc cyanide, apalladium catalyst such asdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct, zinc dust, in a polar aprotic solvent such asDMF at elevated temperature, after reaction work up, typically by aliquid-liquid extraction the intermediate was purified by columnchromatography. The intermediate1H-pyrrolo[2,3-b]pyridine-4-carbonitrile derivative of general formula[I-023] was then reacted with hydroxylamine (50% wt/wt in water) and apolar protic solvent such as EtOH at elevated temperature. Theintermediate N-hydroxy-1H-pyrrolo[2,3-b]pyridine-4-carboxamide ofgeneral formula [I-024] was then subjected to a hydrogenolysis reactionwith acetic anhydride in a polar protic solvent such as methanol apalladium catalyst such as palladium on activated charcoal under aatmosphere of hydrogen gas, to yield the substituted1H-pyrrolo[2,3-b]pyridine-4-carboxamidine derivative of general formula[I-012] Scheme D4.

Synthesis of2-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine; acetic acidsalt [D036]

Step 1: 2-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine [D031]

To a solution of (3-Methyl-pyridin-2-yl)-carbamic acid tert-butyl ester(5 g, 24 mmol) in THF (50 mL) at −30° C. was added BuLi (2.5M, 28.5 mL,72 mmol) and the reaction mixture was warmed to 0° C. and stirred for 90min. A solution of 2,2,2-Trifluoro-N-methoxy-N-methyl-acetamide (2.9 mL,24 mmol) in THF (10 mL) was slowly added and the reaction was stirred at0° C. for 3h. The reaction mixture was slowly treated with HCl (30 mL,6M) followed by heating at 60° C. for 18h. The reaction mixture wascooled, the layers were separated and the aqueous layer was made basicwith NaOH (5M) and extracted twice with AcOEt. The combined organiclayers (plus the one from the first extraction) were dried over MgSO4,concentrated and the residue was purified by Column chromatography(eluent Cyclohexane/AcOEt 1/0 to 8/2) to afford the title compound[D031] as a yellow solid (1.2 g, 27%): LCMS method: 5, RT 4.44 min, MI187 [M+H], NMR: (1H, 500 MHz, d6-dmso) 14.33 (brs, 1H), 8.49 (d, 1H),8.09 (d, 1H), 7.27 (dd, 1H), 6.90 (s, 1H).

2-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide [D032]

To a solution of 2-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine [D031](1.2g, 6.45 mmol) in DCM (10 mL), 3-Chloroperoxybenzoic acid (1.22 g, 7.09mmol) was added and the mixture was stirred overnight. A saturatedsolution of NaHCO3 was added and the layers were separated. The organicwas dried over MgSO4 and concentrated under reduced pressure. To yieldthe title compound [D032] as yellow solid (0.82 g, 63%) was used withoutfurther purification. LCMS method: 5, RT 3.43 min, MI 203 [M+H], NMR:(1H, 500 MHz, d6-dmso) 8.34 (d, 1H), 7.76 (d, 1H), 7.19 (d, 1H), 7.18(s, 1H),

4-Chloro-2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine [D033]

To a solution of 2-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine 7-oxide[D032](0.82 g, 4.05 mmol) in DMF (10 mL) at 50° C., methane sulfonylchloride (1.57 mL, 20.28 mmol) was added dropwise. The solution wasstirred 3h at 50° C. The reaction was then cooled to room temperatureand water (5 mL) was added. A solution of 5M NaOH was added and thesolid was collected, dried using an azeotrope with toluene to yield thetitle compound [D032] which was used without further purification. LCMS:1LCMS5 5.77 min, 221-223 [M+1, Cl pattern].

2-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile [D034]

A seaablel vial was charged with4-Chloro-2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine [D033](0.6 g, 2.72mmol), Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.222 g, 0.27 mmol), zinc cyanide (0.958 g, 8.16mmol), zinc (dust, 0.036 g, 0.54 mmol) and DMF (15 mL). The vial wascapped and heated at 900° C. overnight. The reaction was poured in waterand extracted with AcOEt. The aqueous layer was extracted again withAcOEt and the organics were combined, washed with water and brine anddried over MgSO4 to yield the title compound [D043] which was usedwithout further purification: LCMS method: 5, RT 4.98 min, MI 212 [M+H].

N-Hydroxy-2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine[D035]

A mixture of 2-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile[D034](0.68 g, 3.22 mmol) and hydroxylamine (50% wt/wt in water, 0.205mL, 6.44 mmol) and EtOH (5 mL) was heated at 80° C. overnight. Solventwas then evaporated and the mixture azeotroped twice with toluene undervacuum. To yield the title compound [D035] as a yellow solid (0.78 g,99%) which was used in the next step without further purification: LCMSmethod: 5, RT 2.22 min, MI 245 [M+H], NMR: (1H, 500 MHz, d6-dmso): 13.14(brs, 1H), 10.40 (s, 1H), 8.70 (s, 1H), 7.70 (s, 1H), 7.56 (d, 1H), 6.27(s, 2H).

2-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine; compoundwith acetic acid [D036]

To a suspension ofN-Hydroxy-2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine[D035](0.43 g, 1.76 mmol) in MeOH (10 mL) was added dropwise aceticanhydride (0.175 mL, 1.85 mmol) at room temperature. The suspension wasstirred 15 min and palladium on charcoal (5% wt/wt, 0.1 g) was added.The vessel was seal and hydrogen (balloon) was bubble in the mixture for10 min and left stirring at RT under hydrogen atmosphere overnight. Themixture was filtered through celite and concentrated in vacuo to yieldthe title compound [D036] as a yellow solid (0.51 g, 100%) which wasused without further purification. LCMS method: 5, RT 4.45 min, MI 229[M+H], NMR: (1H, 500 MHz, d6-dmso) 1.79 (s, 3H, CH₃CO₂H), 8.50 (s, 1H),7.35 (s, 1H), 7.03 (s, 1H).

Synthesis of 2-Thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidineacetic acid salt [D042]

2-Thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine [D037]

Was prepared, following the procedure described in scheme D4, step 1, byreaction of (3-Methyl-pyridin-2-yl)-carbamic acid tert-butyl ester,thiophene-2-carboxylic acid methoxy-methyl-amide, BuLi and THF to givethe title compound as a yellow solid. LCMS method: 5, RT 4.79 min, MI201 [M+H].

2-Thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine 7-oxide [D038]

Was prepared, following the procedure described in scheme D4, step 2, byreaction of 2-Thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine [D037], m-CPBA andDCM to give the title compound as a yellow solid. LCMS method: 5, RT3.38 min, MI 217 [M+H].

4-Chloro-2-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine [D039]

Was prepared, following the procedure described in scheme D4, step 3, byreaction of 2-Thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine 7-oxide [D038],methane sulfonyl chloride and DMF to give the title compound as a yellowsolid. LCMS method: 5, RT 6.05 min, MI 235 [M+H].

2-Thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile [D040]

Was prepared, following the procedure described in scheme D4, step 4, byreaction of 4-Chloro-2-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine [D039],PdC12dppf:CH2C12, Zinc cyanide, zinc dust and DMA to give the titlecompound as a yellow solid. LCMS method: 5, RT 5.28 min, MI 226 [M+H].

N-Hydroxy-2-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine[D041]

Was prepared, following the procedure described in scheme D4, step 5, byreaction of 2-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile[D040], hydroxylamine and EtOH to give the title compound as a yellowsolid. LCMS method: 5, RT 2.38 min, MI 259 [M+H].

2-Thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine acetic acidsalt [D042]

Was prepared, following the procedure described in scheme D4, step 6, byreaction ofN-Hydroxy-2-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidineaceticanhydride [D041], Pd/C, hydrogen and MeOH to give the title compound asa yellow solid. LCMS method: 5, RT 4.45 min, MI 243 [M+H].

Synthesis of 2-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine aceticacid salt [D045]

2-Methyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile [D043]

Was prepared, following the procedure described in scheme D4, step 4, byreaction of 4-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine,PdCl2dppf:CH2Cl2, Zinc cyanide, zinc dust and DMA to give the titlecompound as a white solid. LCMS method: 5, RT 4.17 min, MI 158 [M+H].

N-Hydroxy-2-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine [D044]

Was prepared, following the procedure described in scheme D4, step 5, byreaction of 2-Methyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile [D043],hydroxylamine and EtOH to give the title compound as a yellow solid.LCMS method: 5, RT 1.92 min, MI 191 [M+H].

2-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine acetic acid salt[D045]

Was prepared, following the procedure described in scheme D4, step 6, byreaction of N-Hydroxy-2-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine[D044], acetic anhydride, Pd/C, hydrogen and MeOH to give the titlecompound as a yellow solid. LCMS method: 5, RT 2.44 min, MI 175 [M+H].

For example Synthesis of 21H-pyrrolo[2,3-b]pyridine-4-carboxamidineacetic acid salt [D047]

N-Hydroxy-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine [D047]

Was prepared, following the procedure described in scheme D4, step 5, byreaction of 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile, hydroxylamine andEtOH to give the title compound as a yellow solid. LCMS method: 5, RT1.24 min, MI 162 [M+H].

2-1H-pyrrolo[2,3-b]pyridine-4-carboxamidine acetic acid salt [D047]

Was prepared, following the procedure described in scheme D4, step 6, byreaction of N-Hydroxy-1 1H-pyrrolo[2,3-b]pyridine-4-carboxamidine[D047], acetic anhydride, Pd/C, hydrogen and MeOH to give the titlecompound as a yellow solid. LCMS method: 5, RT 1.23 min, MI 161 [M+H],NMR: (1H, 500 MHz, d6-dmso) 8.38 (1H, d), 7.71 (1H, d), 7.30 (1H, d),6.58 (1H, d), 1.80 (8H, s)

Following the procedures described in Example AZA-9, the followingcompounds were prepared from 3-Cyclopropyl-5-fluoro-isonicotinic acid:

SM Amidine Amine Analysis Ex [I-013] [I-014] [I-017] LCMS NMR Name 1212[D015]

Method 5: RT: 3.59 min, MI: 440 [M + H] 1H NMR (DMSO, 500 MHz) 13.17 (s,1H), 9.19 (s, 1H), 8.63 (d, 1H), 8.25 (d, 1H), 8.19 (s, 1H), 7.95 (s,1H), 4.10- 3.77 (m, 8H), 2.75- 2.69 (m, 1H), 1.28- 1.22 (m, 2H), 1.13-1.07 (m, 2H). [5-Cyclopropyl- 4-piperazin-1- yl-2-(2- trifluoromethyl-1H-pyrrolo[2,3- b]pyridin-4-yl)- pyrido[3,4- d]pyrimidine 1213 [D015]

Method 5: RT: 5.02 min, MI: 440 [M + H] 1H NMR (400 MHz, d6-DMSO, 90°C.) 11.49 (1H, br. s), 9.10 (1H, s), 8.39 (1H, d, J = 5.0 Hz), 8.16 (1H,s), 8.10 (1H, d, J = 5 Hz), 7.57 (1H, t, J = 2.9 Hz), 7.46 (1H, dd, J =3.3, 1.9 Hz) 4.43 (1H, br. d, J = 12.8 Hz), 5-Cyclopropyl- 2-(1H-pyrrolo[2,3- b]pyridin-4-yl)- 4-((R)-3- trifluoro- methyl-piperazin-1-yl)- pyrido[3,4- d]pyrimidine 4.01-3.96 (1H, m), 3.77-3.72(1H, m), 3.48-3.38 (2H, m), 3.10-3.07 (1H, m), 2.93-2.85 (1H, m),2.75-2.70 (1H, m), 1.34-1.20 (2H, m), 1.08-0.96 (2H, m). 1214 [D015]

Method 5: RT: 5.03 min, MI: 440 [M + H] (1H, 400 MHz, d6- dmso 90° C.)11.49 (1H, brs), 9.10 (1H, s), 8.39 (1H, d), 8.16 (1H, s), 8.10 (1H, d),7.57 (1H, t), 7.46 (1H, dd) 4.43 (1H, br. d), 4.01-3.96 (1H, m),3.77-3.72 (1H, m), 3.48-3.38 (2H, m), 3.10-3.07 (1H, 5-Cyclopropyl-2-(1H- pyrrolo[2,3- b]pyridin-4-yl)- 4-((S)-3- trifluoro- methyl-piperazin-1-yl)- pyrido[3,4- d]pyrimidine m), 2.93-2.85 (1H, m),2.75-2.70 (1H, m), 1.34-1.20 (2H, m), 1.08-0.96 (2H, m). 1215 [D015]

Method 5: RT: 5.27 min, MI: 454 [M + H] 1H NMR (DMSO, 500 MHz), 11.67(brs, 1H), 9.07 (brs, 1H), 8.24 (d, 1H), 8.10 (s, 1H), 8.03 (d, 1H),7.16 (s, 1H), 4.72- 4.18 (m, 1H), 4.05- 3.88 (m, 1H), 3.85- 3.61 (m,1H), 3.31 (s, 3H), 3.18-2.72 (m, 4H), 1.33-1.14 (m, 5-Cyclopropyl-2-(2-methyl- 1H-pyrrolo[2,3- b]pyridin-4-yl)- 4-(3-trifluoro- methyl-piperazin-1-yl)- pyrido[3,4- d]pyrimidine 2H), 1.06-0.95 (m, 1H). 1216[D015]

Method 5: RT: 3.20 min, MI: 426 [M + H] 1H NMR (DMSO, 500 MHz) 11.68(brs, 1H), 9.07 (brs, 1H), 8.24 (d, 1H), 8.13 (d, 1H), 8.11 (d, 1H),7.17 (s, 1H), 4.34- 4.08 (m, 2H), 3.60- 3.46 (m, 2H), 3.18- 2.84 (m,2H), 3.01 (s, 3H), 1.04-0.88 (m, 3H), 0.60-0.25 (m, 5-Cyclopropyl-4-((S)-3- cyclopropyl- piperazin-1-yl)- 2-(2-methyl- 1H-pyrrolo[2,3-b]pyridin-4-yl)- pyrido[3,4- d]pyrimidine 5H). 1217 [D015]

Method 5: RT: 2.80 min, MI: 386 [M + H] (1H, 500 MHz, d6- dmso) 11.64(s, 1H), 9.03 (s, 1H), 8.22 (d, 1H), 8.06 (s, 1H), 8.02 (d, 1H), 7.15(s, 1H), 3.08 (very broad m, 4H), 2.87-2.92 (m, 4H), 2.65-2.70 (m, 1H),2.47 (s, 3H), 1.22-1.26 (m, 2H), 5-Cyclopropyl- 2-(2-methyl-1H-pyrrolo[2,3- b]pyridin-4-yl)- 4-piperazin-1- yl-pyrido[3,4-d]pyrimidine 1.02-1.07 (m, 2H), 1218 [D015]

Method 5: RT: 5.03 min, MI: 440 [M + H] 1H NMR (400 MHz, d6-DMSO, 90°C.) 11.49 (1H, br. s), 9.10 (1H, s), 8.39 (1H, d, J = 5.0 Hz), 8.16 (1H,s), 8.10 (1H, d, J = 5 Hz), 7.57 (1H, t, J = 2.9 Hz), 7.46 (1H, dd, J =3.3, 1.9 Hz) 4.43 (1H, br. d, J = 12.8 Hz), 5-Cyclopropyl- 2-(1H-pyrrolo[2,3- b]pyridin-4-yl)- 4-(3- trifluoromethyl- piperazin-1-yl)-pyrido[3,4- d]pyrimidine 4.01-3.96 (1H, m), 3.77-3.72 (1H, m), 3.48-3.38(2H, m), 3.10-3.07 (1H, m), 2.93-2.85 (1H, m), 2.75-2.70 (1H, m),1.34-1.20 (2H, m), 1.08-0.96 (2H, m). 1219 [D015]

Method 5: RT: 3.53 min, MI: 462 [M + H] (1H, 500 MHz, d6- dmso) 11.47(1H, brs), 9.05 (1H, s), 8.35 (1H, d), 8.06 (1H, s), 7.95 (1H, d),7.56-7.55 (1H, br. m), 7.43 (1H, d), 7.34-7.30 (2H, m), 7.27-7.24 (3H,m), 4.27 (1H, dr. d), 4.20-4.17 (1H, m), 4-((S)-3- Benzyl-piperazin-1-yl)- 5-cyclopropyl- 2-(1H- pyrrolo[2,3- b]pyridin-4-yl)-pyrido[3,4- d]pyrimidine 3.39-3.33 (1H, m), 3.21-3.17 (1H, m), 3.14-3.04(2H, m), 2.96-2.82 (2H, m), 2.77-2.72 (1H, m), 2.63-2.56 (1H, m),1.23-1.15 (2H, m), 0.94-0.87 (2H, m). 1220 [D015]

Method 5: RT: 3.09 min, MI: 412 [M + H] (1H, 500 MHz, d6- dmso) 11.52(1H, s, brs), 9.13 (1H, s), 8.41 (1H, d), 8.20 (1H, s), 8.11 (1H, d),7.60 (1H, d), 7.47 (1H, d), 4.44-4.41 (1H, br. m), 4.28-4.24 (1H, br.m), 3.74-3.68 (1H, br. m), 3.60- 5-Cyclopropyl- 4-((S)-3- cyclopropyl-piperazin-1-yl)- 2-(1H- pyrrolo[2,3-b] pyridin-4-yl)- pyrido[3,4-d]pyrimidine 3.53 (1H, m), 3.36- 3.33 (1H, m), 3.14- 3.07 (1H, m), 2.80-2.68 (2H, m), 1.30- 1.24 (2H, m), 1.12- 1.04 (2H, m), 1.02- 0.97 (1H,m), 0.66- 0.59 (3H, m), 0.46- 0.41 (1H, m). 1221 [D015]

Method 5: RT: 2.94 min, MI: 411 [M + H] (1H, 400 MHz, d6- dmso 90° C.)11.46 (1H, brs), 9.08 (1H, s), 8.38 (1H, d), 8.15 (1H, s), 8.13 (1H, d),7.57-7.55 (1H, m), 7.48 (1H, dd), 4.34- 4.32 (1H, m), 4.13- 4.10 (1H,m), 3.31- 3.25 (1H, m), 3.21- 3.16 (1H, m), 3.11- {(S)-4-[5-Cyclopropyl-2- (1H- pyrrolo[2,3- b]pyridin-4-yl)- pyrido[3,4-d]pyrimidin-4- yl]-piperazin-2- yl}-acetonitrile 3.01 (2H, m), 2.95-2.86 (2H, m), 2.72- 2.69 (1H, m), 2.61- 2.58 (1H, m), 1.30- 1.23 (2H,m), 1.03- 0.98 (2H, m).

The following compounds were synthesised according to the generalsynthesis shown in scheme [B4]

Analysis Ex Amine 1 Amidine 2 LCMS NMR Name 1222

method 5: RT 3.59 min, MI: 454 [MH+] NHM, CDCl3, 500 MHz, 12.06 (brs,1H), 9.12 (s, 1H), 8.47 (d, 1H), 8.23 (d, 1H), 8.06 (s, 1H), 7.80 (s,1H), 7.57 (d, 1H), 7.39 (d, 1H), 7.19 (dd, 1H), 4.02-3.61 (m, 4H), 3.12-3.06 (m, 4H), 2.80-2.74 (m, 1H), 1.30-1.26 (m, 2H), 1.05- 1.015-Cyclopropyl-4- piperazin-1-yl-2- (2-thiophen-2-yl- 1H-pyrrolo[2,3-b]pyridin-4-yl)- pyrido[3,4- d]pyrimidine 1223

method 5: RT 3.21 min, MI: 412 [MH+] 1H NMR (400 MHz, 90° C., d6-DMSO)11.27 (1H, br s), 9.04 (1H, s), 8.23 (1H, d, J = 5.1 Hz), 8.11 (1H, s),8.02 (1H, d, J = 5.1 Hz), 7.10 (1H, s), 3.74-3.72 (4H, m), 2.95- 2.92(4H, m, overlapping with water signal), 2.74-2.67 (1H, m), 2.18-2.12(1H, m), 1.28- 5-Cyclopropyl-2- (2-cyclopropyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-4- piperazin-1-yl- pyrido[3,4- d]primidine 1.23 (2H, m),1.09-1.04 (2H, m), 1.00-0.96 (2H, m), 0.95- 0.91 (2H, m). 1224

method 5: RT 4.98 min, MI: 412 [MH+] NMR 1H DMSO 13.11 (brs, 1H), 9.12(s, 1H), 8.60 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.94 (s, 1H),40.08-4.05 (m, 1H), 3.95-3.55 (m, 8H), 1.26-1.17 (m, 2H), 1.56-1.00 (m,2H) 4-[5-Cyclopropyl- 2-(2- trifluoromethyl- 1H-pyrrolo[2,3-b]pyridin-4-yl)- pyrido[3,4- d]pyrimidin-4-yl]- piperazine-1- carboxylicacid ethyl ester 1225 —

method 5: RT 5.77 min, MI: 372 [MH+] NMR 1H DMSO 8.97 (s, 1H), 8.62 (d,1H), 8.24 (s, 1H), 7.88 (d, 1H), 7.67 (s, 1H), 3.45- 3.39 (m, 1H),1.12-1.08 (m, 2H), 0.97-0.92 (m, 2H). 5-Cyclopropyl-2-(2-trifluoromethyl- 1H-pyrrolo[2,3- b]pyridin-4-yl)- pyrido[3,4-d]pyrimidin-4-ol 1226

method 5: RT 2.10 min, MI: 390 [MH+] 1H NMR (500 MHz, d6- DMSO) 11.92(1H, s), 8.98 (1H, s), 8.32 (1H, d, J = 3.5 Hz), 8.12 (1H, s), 7.65 (1H,t, J = 2.9 Hz), 6.94 (1H, dd, J = 3.4, 2.0 Hz), 3.84-3.49 (4H, br m),2.85 (4H, br s), 2.67- 2.62 (1H, m), 1.29-1.26 (2H, m), 1.07-1.04 (2H,m). 5-Cyclopropyl-2- (5-fluoro-1H- pyrrolo[2,3- b]pyridin-4-yl)-4-piperazin-1-yl- pyrido[3,4- d]pyrimidine 1227

method 5: RT 6.01 min, MI: 441 [MH+] NMR 1H DMSO 13.11 (s, 1H), 9.12 (s,1H), 8.62 (s, 1H), 8.22 (d, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 3.80-3.60(m, 8H), 2.72-2.67 (m, 1H), 1.28- 1.23 (m, 2H), 1.06-1.03 (m, 2H).5-Cyclopropyl-4- morpholin-4-yl-2- (2-trifluoromethyl- 1H-pyrrolo[2,3-b]pyridin-4-yl)- pyrido[3,4- d]pyrimidine 1228

method 5: RT 2.16 min, MI: 389 [MH+] 1H NMR (400 MHz, d6- DMSO, 90° C.)11.28 (1H, s), 9.04 (1H, s), 8.24 (1H, d, J = 5.2 Hz), 8.11 (1H, s),8.03 (1H, d, J = 5.2 Hz), 7.16 (1H, d, J = 1.5 Hz), 3.74-3.72 (4H, m),2.95-2.93 (4H, m, overlapping with water signal), 2.74-2.69 (1H, m),5-Cyclopropyl-4- piperazin-1-yl-2- (2- triduteriomethyl- 1H-pyrrolo[2,3-b]pyridin-4-yl)- pyrido[3,4- d]pyrimidine 1.28-1.23 (2H, m), 1.01- 0.97(2H, m). 1229

method 5: RT 3.44 min, MI: 462 [MH+] 1H NMR (d6-DMSO, 500 MH), 11.87(1H, s), 8.94 (1H, s), 8.22 (1H, s), 8.11 (1H, s), 3.75-3.55 (4H, m),2.82 (4H, br s), 2.64-2.59 (1H, m), 1.27 (2H, ddd), 1.05 (2H, ddd)2-(2-tert-Butyl-5- chloro-1H- pyrrolo[2,3- b]pyridin-4-yl)-5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidine 1230

method 5: RT: 4.02 min, MI: 466 [M + H] 1H NMR (400 MHz, d6- DMSO, 90°C.) 9.13 (1H, s), 8.38 (1H, d, J = 5.1 Hz), 8.14 (1H, s), 8.11 (1H, d, J= 5.1 Hz), 8.07-8.03 (2H, m), 7.84 (1H, s), 7.32 (2H, t, J = 8.9 Hz),3.78-3.76 (4H, m), 2.97- 2.94 (4H, m, overlapping with water signal),2.77-2.70 5-Cyclopropyl-2- [2-(4-fluoro- phenyl)-1H- pyrrolo[2,3-b]pyridin-4-yl]-4- piperazin-1-yl- pyrido[3,4- d]pyrimidine (1H, m),1.30-1.25 (2H, m), 1.02-0.98 (2H, m). 1231

method 5: RT: 3.51 min, MI: 428 [M + H] NMR: (1H, d6-DMSO, 500 MHz)11.71 (1H, br s), 9.03 (1H, s), 8.26 (1H, d), 8.07 (1H, s), 8.02 (1H,d), 7.18 (1H, d), 3.81 (2H, v br s), 3.62 (2H, v br s), 2.90 (4H, br s),2.70-2.65 (1H, m), 1.41 (9H, s), 1.28-1.22 (2H, m), 1.04- 1.01 (2H, dt).2-(2-tert-Butyl-1H- pyrrolo[2,3- b]pyridin-4-yl)-5- cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidine 1232

method 5: RT 2.48 min, MI: 458 [MH+] 1H NMR (400 MHz, d6- DMSO, 90° C.)9.02 (1H, s), 8.54 (1H, d, J = 3.6 Hz), 8.18 (1H, s), 7.51-7.49 (1H, m),3.74-3.72 (4H, m), 2.92- 2.89 (4H, m), 2.68-2.62 (1H, m), 1.31-1.26 (2H,m), 1.04- 1.01 (2H, m). 5-Cyclopropyl-2- (5-fluoro-2- trifluoromethyl-1H-pyrrolo[2,3- b]pyridin-4-yl)-4- piperazin-1-yl- pyrido[3,4-d]pyrimidine 1233

method 5: RT: 3.63 min, MI = 454 [M + H] 5-Cyclopropyl-4- ((S)-3-methyl-piperazin-1-yl)-2- (2-trifluoromethyl- 1H-pyrrolo[2,3- b]pyridin-4-yl)-pyrido[3,4- d]pyrimidine 1234

471.1 (M + H) (CDCl₃) 13.11 (br s, 1H), 9.06 (s, 1H), 8.62 (d, J = 5.0Hz, 1H), 8.25 (d, J = 5.0 Hz, 1H), 8.10 (s, 1H), 7.98 (d, J = 1.0 Hz,1H), 5.09-4.67 (m, 1H), 4.67-4.17 (m, 2H), 4.03-3.68 (m, 4H), 3.68-3.38(m, 2H), 2.63-2.53 (m, 1H), 2.06 (br s, 1H), 1.70 (br s, water), 1.49-(+/−)-(cis)-1-[5- Cyclopropyl-2-(2- trifluoromethyl- 1H-pyrrolo[2,3-b]pyridin-4-yl)- pyrido[3,4- d]pyrimidin-4-yl]- piperidine-3,4-diol 0.80(m, 4H) 1235

471.1 (M + H) (CDCl₃): 13.09 (br s, 1H), 9.07 (s, 1H), 8.62 (d, J = 5.0Hz, 1H), 8.25 (d, J = 5.0 Hz, 1H), 8.11 (s, 1H), 7.98 (d, J = 1.0 Hz,1H), 5.22-4.71 (m, 2H), 4.22-3.74 (m, 3H), 3.62- 3.34 (m, 3H), 2.60-2.53(m, 1H), 2.30-1.81 (m, 1H), 1.71- 1.13 (m, 3H), 1.12-0.95 (m,(+/−)-(trans)-1-[5- Cyclopropyl-2-(2- trifluoromethyl- 1H-pyrrolo[2,3-b]pyridin-4-l)- pyrido[3,4- d]pyrimidin-4-yl]- piperidine-3,4-diol 2H)1236

method 5: RT: 4.74 min, MI 508 [M + H] 1H NMR (DMSO, 500 MHz) 13.14 (s,1H), 9.12 (s, 1H), 8.61 (d, 1H), 8.21 (d, 1H), 8.14 (s, 1H), 7.91 (s,1H), 4.70-4.21 (m, 1H), 4.04-3.96 (m, 1H), 3.87-3.46 (m, 2H), 3.19-2.96(m, 3H), 1.37-1.17 (m, 2H), 1.14-0.96 (m, 2H). 5-Cyclopropyl-4-(3-trifluoromethyl- piperazin-1-yl)-2- (2-trifluoromethyl-1H-pyrrolo[2,3- b]pyridin-4-yl)- pyrido[3,4- d]pyrimidine 1237

439.49 5-Cyclopropyl-4- piperidin-1-yl-2-(2- trifluoromethyl-1H-pyrrolo[2,3- b]pyridin-4-yl)- pyrido[3,4- d]pyrimidine 1238

method 5: RT: 5.31 min, MI 480 [M + H] 1H NMR (400 MHz, d6- DMSO, 90°C.) 11.66 (1H, br s), 9.04 (1H, s), 8.39 (1H, d, J = 5.0 Hz), 8.13 (1H,s), 8.10 (1H, d, J = 5.0 Hz), 7.55 (1H, s), 3.76-3.73 (4H, m), 2.94-2.91 (4H, m, partly obscured by water signal), 2.73-2.66 (1H, m),1.49-1.48 (2H, m), 5-Cyclopropyl-4- piperazin-1-yl-2- [2-(1-trifluoromethyl- cyclopropyl)-1H- pyrrolo[2,3- b]pyridin-4-yl]-pyrido[3,4- d]pyrimidine 1.47-1.46 (2H, m), 1.29- 1.24 (2H, m),1.01-0.97 (2H, m). 1239

method 5: RT 6.34 min, MI = 455 [M + H] NMR 1H DMSO 13.12 (s, 1 H), 9.08(s, 1H), 8.61 (d, 1H), 8.23 (d, 1H), 8.10 (s, 1H), 7.96 (s, 1H),4.84-4.70 (m, 1H), 4.14-4.04 (m, 1H), 3.88-3.75 (m, 1H), 3.68-3.40 (m,2H), 1.95-1.84 (m, 1H), 1.67-1.39 (m, 2H), 1.31-1.20 (m, 2H), 1.17-0.99(m, 4H). 1-[5-Cyclopropyl- 2-(2- trifluoromethyl- 1H-pyrrolo[2,3-b]pyridin-4-yl)- pyrido[3,4- d]pyrimidin-4-yl]- piperidin-4-ol 1240

method 5: RT: 3.82 min, MI: 488 [M + H] 1H NMR (400 MHz, d6- DMSO, 90°)11.28 (1H, br s), 8.96 (1H, s), 8.27 (1H, d, J = 5.1 Hz), 8.09 (1H, s),8.05 1H, d, J = 5.1 Hz), 7.45-7.43 (2H, m), 7.38-7.34 (2H, m), 7.29-7.26 (1H, m), 7.02 (1H, m), 3.63-3.60 (4H, m), 2.88- 2.85 (4H, m),2.70-2.64 (1H, 5-Cyclopropyl-2- [2-(1-phenyl- cyclopropyl)-1H-pyrrolo[2,3- b]pyridin-4-yl]-4- piperazin-1-yl- pyrido[3,4- d]pyrimidinem), 1.60-1.57 (2H, m), 1.40- 1.37 (2H, m), 1.27-1.22 (2H, m), 1.00-0.96(2H, m). 1241

method 5: RT 5.38 min, MI = 464 [M + H] NMR 1H DMSO, 90°C.,, 12.78 (brs,1H), 9.12 (s, 1H), 8.62 (d, 1H), 8.24 (d, 1H), 8.18 (s, 1H), 7.95 (d,1H), 4.04-3.98 (m, 2H), 3.72-3.66 (m, 2H), 3.22-3.15 (m, 1H), 2.72-2.65(m, 1H), 2.15-2.08 (m, 2H), 2.00-1.91 (m, 2H), 1.31-1.26 (m, 2H),1.03-0.99 1-[5-Cyclopropyl- 2-(2- trifluoromethyl- 1H-pyrrolo[2,3-b]pyridin-4-yl)- pyrido[3,4- d]pyrimidin-4-yl]- piperidine-4-carbonitrile (m, 2H). 1242

method 5: RT: 5.29 min, MI = 469 [M + H] NMR 1H DMSO, 90°C., 12.76 (brs,1H), 9.08 (s, 1H), 8.61 (d, 1H), 8.25 (d, 1H), 8.16 (s, 1H), 7.96 (d,1H), 4.38-4.35 (m, 2H), 4.12 (t, 1H), 3.37- 3.28 (m, 4H), 2.69-2.62 (m,1H), 1.91-1.73 (m, 3H), 1.46- 1.34 (m, 2H), 1.29-1.25 (m, 2H), 1.02-0.98(m, 2H). {1-[5-Cyclopropyl- 2-(2- trifluoromethyl- 1H-pyrrolo[2,3-b]pyridin-4-yl)- pyrido[3,4- d]pyrimidin-4-yl]- piperidin-4-yl}-methanol 1243

method 5: RT 4.57 min, MI: 441 [M + H] NMR 1H DMSO, 90° C., 9.03 (s,1H), 8.60 (d, 1H), 8.26 (d, 1H)m, 8.19 (s, 1H), 7.96 (d, 1H), 4.53 (t,2H), 4.26 (dd, 2H), 3.62 (d, 2H), 3.00-2.87 (m, 2H), 1.32-1.28 (m, 2H),0.97-0.93 (m, 2H). {1-[5-Cyclopropyl- 2-(2- trifluoromethyl-1H-pyrrolo[2,3- b]pyridin-4-yl)- pyrido[3,4- d]pyrimidin-4-yl]-azetidin-3-yl}- methanol 1244

method 5: RT = 5.05 min, MI: 503 [M + H] 1H NMR (400 MHz, d6- DMSO, 90°C.) 11.27 (1H, s), 8.95 (1H, s), 8.26 (1H, d, J = 5.1 Hz), 8.09 (1H, s),8.05 (1H, d, J = 5.1 Hz), 7.45-7.42 (2H, m), 7.37-7.34 (2H, m),7.29-7.25 (1H, m), 7.05 (1H, d, J = 2.2 Hz), 4.40 (1H, d, J = 4.3 Hz),4.01-3.95 (2H, m), 1-[5-Cyclopropyl- 2-[2-(1-phenyl- cyclopropyl)-1H-pyrrolo[2,3- b]pyridin-4-yl]- pyrido[3,4- d]pyrimidin-4-yl}-piperidin-4-ol 3.83-3.77 (1H, m), 3.45- 3.38 (2H, m), 2.66-2.61 (1H, m),1.90-1.83 (2H, m), 1.59- 1 .49 (4H, q and m overlapping), 1.39-1.37 (2H,m), 1.26-1.21 (2H, m), 0.99- 0.95 (2H, m). 1245

method 5: RT 4.51 min, MI: 489 [M + H] 1H NMR (DMSO, 500 MHz) 13.15 (s,1H), 9.19 (s, 1H), 8.63 (d, 1H), 8.25 (d, 1H), 8.16 (s, 1H), 7.97 (s,1H), 4.41-4.01 (m, 4H), 3.41-3.34 (m, 4H), 2.73-2.66 (m, 1H), 1.32-1.23(m, 2H), 1.09-1.02 (m, 2H). 5-Cyclopropyl-4- (1,1-dioxo-1λ⁶-thiomorpholin-4- yl)-2-(2- trifluoromethyl- 1H-pyrrolo[2,3-b]pyridin-4-yl)- pyrido[3,4- d]pyrimidine 1246

method 5: RT 5.95 min, MI = 457 [M + H] 1H NMR (DMSO, 500 MHz) 13.12 (s,1H), 9.10 (s, 1H), 8.61 (d, 1H), 8.22 (d, 1H), 8.11 (s, 1H), 7.94 (s,1H), 4.09-4.01 (m, 4H), 2.83-2.73 (m, 4H), 2.63-2.57 (m, 1H), 1.31-1.23(m, 2H), 1.06-0.98 (m, 2H). 5-Cyclopropyl-4- thiomorpholin-4- yl-2-(2-trifluoromethyl- 1H-pyrrolo[2,3- b]pyridin-4-yl)- pyrido[3,4-d]pyrimidine 1247

method 5: RT: 5.61 min, MI: 443 [M + H] 1H NMR (400 MHz, d6- DMSO, 90°C.) 11.31 (1H, br s), 9.03 (1H, s), 8.27 (1H, d, J = 5.2 Hz), 8.11 (1H,s), 8.06 (1H, d, J = 5.2 Hz), 7.24-7.23 (1H, m), 4.42 (1H, d, J = 4.1Hz), 4.18-4.08 (2H, m), 3.88- 3.83 (1H, m), 360-3.53 (2H, m), 2.71-2.65(1H, m), 1-[2-(2-tert-Butyl- 1H-pyrrolo[2,3- b]pyridin-4-yl)-5-cyclopropyl- pyrido[3,4- d]pyrimidin-4-yl]- piperidin-4-ol 1.95-1.91(2H, m), 1.65- 1.57 (2H, m), 1.46 (9H, s), 1.28-1.23 (2H, m), 1.00- 0.96(2H, m). 1248

method 5: RT: 5.62 min, MI: 411 [M + H] 1H NMR (DMSO, 500 MHz) 13.09(brs, 1H), 9.02 (s, 1H), 8.59 (d, 1H), 8.24 (d, 1H), 8.13 (s, 1H), 7.95(s, 1H), 7.47 (t, 4H), 2.43-2.33 (m, 3H), 1.31-1.24 (m, 2H), 0.99-0.92(m, 2H). 4-Azetidin-1-yl-5- cyclopropyl-2-(2- trifluoromethyl-1H-pyrrolo[2,3- b]pyridin-4-yl)- pyrido[3,4- d]pyrimidine 1249

method 5: RT: 1.76 min, MI: 456 [M + H] 1H NMR (400 MHz, d6- DMSO, 90°C.) 11.31 (1H, s), 9.05 (1H, s), 8.28 (1H, d, J = 5.0 Hz), 8.15 (1H, s),8.06 (1H, d, J = 5.0 Hz), 7.29-7.26 (1H, m), 7.19 (1H, d, J = 2.3 Hz),4.03-4.00 (2H, m), 3.96- 3.94 (2H, m), 3.39-3.35 (2H, m), 2.77-2.74 (2H,m), 1-[2-(2-tert-Butyl- 1H-pyrrolo[2,3- b]pyridin-4-yl)-5- cyclopropyl-pyrido[3,4- d]pyrimidin-4-yl]- [1,4]diazepan-5- one 2.65-2.58 (1H, m),1.47 (9H, s), 1.28-1.23 (2H, m), 0.99- 0.95 (2H, m). 1250

method 5: RT: 4.78 min, MI: 429 [M + H] 1H NMR (500 MHz, d6- DMSO),11.67 (1H, br d, J = 1.8 Hz), 8.92 (1H, s), 8.25 (1H, d, J = 5.2 Hz),8.07 (1H, s), 8.06 (1H, d, J = 5.2 Hz), 7.22 (1H, d ,J = 2.3 Hz), 4.95(1H, br, J = 2.9 Hz), 4.35 (1H, br s), 4.19-4.13 (1H, m), 4.09-(R)-1-[2-(2-tert- Butyl-1H- pyrrolo[2,3- b]pyridin-4-yl)-5- cyclopropyl-pyrido[3,4- d]pyrimidin-4-yl]- pyrrolidin-3-ol 4.04 (1H, s), 3.77-3.72(1H, m), 3.48 (1H, d, J = 11.3 Hz), 2.35-2.28 (1H, m), 2.05- 1.98 (1H,m), 1.90-1.86 (1H, m), 1.34-1.29 (1H, m), 1.20- 1.14 (1H, m), 1.20-1.14(1H, m), 1.04-0.99 (1H, m), 0.94- 0.89 (1H, m). 1251

method 5: RT: 3.79 min, MI: 468 [M + H] 1H NMR (DMSO, 500 MHz) 13.10(brs, 1H), 9.06 (s, 1H), 8.61 (d, 1H), 8.23 (d, 1H), 8.11 (s, 1H), 7.96(s, 1H), 4.02-3.75 (m, 1H), 3.70-3.53 (m, 2H), 3.38-3.25 (m, 2H),2.98-2.85 (m, 2H), 1.29-0.70 (m, 10H). 5-Cyclopropyl-4- (3,3-dimethyl-piperazin-1-yl)-2- (2-trifluoromethyl- 1H-pyrrolo[2,3- b]pyridin-4-yl)-pyrido[3,4- d]pyrimidine 1252

442 1H NMR (400 MHz, d6- DMSO, 90° C.) 8.96 (1H, s), 8.10 (1H, s), 7.82(1H, d, J = 5.5 Hz), 7.34 (1H, d, J = 5.5 Hz), 6.42 (1H, s), 3.70-3.67(2H, m), 3.09-3.106 (2H, m), 2.90-2.88 (2H, m), 2.70- 2.66 (3H, m),1.73-1.58 (7H, m), 1.55-1.45 (4H, m), 1.28- 4-(5-cyclopropyl-4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2- yl)spiro[1,3-dihydropyrrolo[2,3- b]pyridine-2,1′- cyclohexane] 1.20 (3H, m),0.99-0.95 (2H, m). 1253

422 (M + H) ¹H-NMR (DMSO-d₆, 400 MHz): δ 12.08 (s, 1H), 9.17 (s, 1H),8.83 (br s, 1H), 8.68 (d, 1H, J = 8.4 Hz), 8.59 (d, 1H, J = 5.1 Hz),8.26 (s, 1H), 7.89 (d, 1H, J = 5.1 Hz), 7.55 (d, 1H, J = 7.9 Hz), 7.49(m, 1H), 7.18 (m, 1lH), 3.68 (br s, 4H), 3.34 (br s, 4H), 2.77 (m, 1H),4-(5-Cyclopropyl- 4-piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-9H-pyrido[2,3- b]indole 1.30 (m, 2H), 1.14 (m ,2H). 1254

437 (M + H) ¹H-NMR (DMSO-d₆, 400 MHz): δ 12.12 (s, 1H), 9.07 (s, 1H),8.60 (d, 1H, J = 5.0 Hz) 8.54 (d, 1H, J = 8.1 Hz), 8.22 (s, 1H), 7.84(d, 1H, J = 5.0 Hz), 7.56 (d, 1H, J = 8.0 Hz), 7.49 (m, 1H), 7.17 (m,1H), 4.11 (m, 3H), 3.58 (br s, 2H), 2.61 (m, 1H), 1.89 (m, 2H),1-[5-Cyclopropyl- 2-(9H-pyrido[2,3- b]indol-4-yl)- pyrido[3,4-d]pyrimidine-4-yl]- piperidin-4-ol 1.55 (m, 2H), 1.92 (m, 2H), 1.21 (m,2H). 1255

450 (M + H) ¹H-NMR (DMSO-d₆, 400 MHz): δ 12.09 (s, 1H), 9.17 (s, 1H),9.05 (br s, 2H), 8.67 (d, 1H, J = 8.1 Hz), 8.60 (d, 1H, J = 5.1 Hz),8.29 (s, 1H), 7.93 (d, 1H, J = 5.1 Hz) 7.55 (d, 1H, J = 7.9 Hz), 7.49(m, 1H), 7.18 (m, 1H), 3.93 (m, 4H), 3.39 (m, 2H), 2.61 (m,1H),4-[5-Cyclopropyl- 4-(3,3-dimethyl- piperazin-1-yl)- pyrido[3,4-d]pyrimidin-2-yl]- 9H-pyrido[2,3- b]indole 1.01-1.48 (m, 10H).

Example 12534-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-9H-pyrido[2,3-b]indole trifluoroacetic acid salt

1253a) A mixture of azeotropically dried (xylene)4-chloro-9H-pyrido[2,3-b] indole (1.31 g, 6.46 mmol), zinc cyanide (1.21g, 10.3 mmol), zinc (0.145 g, 2.22 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.479 g, 0.523 mmol) and1,1′-bis(diphenylphosphino)ferrocene (0.375 g, 0.676 mmol) inN,N-dimethylformamide (27 mL) was vacuum degassed then heated at 100 OCunder an atmosphere of argon overnight. The mixture is cooled and pouredinto water:ethyl acetate (2:1, 150 mL). The layers were separated, theaqueous extracted with ethyl acetate (2×50 mL) and the combined organicextracts are diluted with hexane (15 mL) and brine (100 mL). The finesuspension of solids was removed by filtration of the aqueous layerthrough Celite, washing with methanol and ethyl acetate. The organicextracts and aqueous/organic rinsate were combined, separated and theorganic layer washed with additional brine (100 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo onto silica gel(12 g) prior to purification on silica gel (80 g, 5-35% ethylacetate:hexane). 9H-Pyrido[2,3-b] indole-4-carbonitrile was isolated asa yellow solid (0.830 g, 66% yield). LCMS (ESI): 194 (M+H)⁺; ¹H-NMR(DMSO-d₆, 400 MHz): δ 12.45 (s, 1H), 8.63 (d, 1H, J=5.0 Hz), 8.32 (d,1H, J=8.0 Hz), 7.68 (d, 1H, J=5.0 Hz), 7.64 (m, 2H), 7.40 (m, 1H);¹³C-NMR (DMSO-d₆, 100 MHz): δ 151.6, 146.2, 139.7, 128.6, 121.1, 120.5,117.9, 116.9, 116.7, 114.1, 112.0, 109.8.

1253b) Lithium hexamethyldisilazide in tetrahydrofuran(1.0 M, 7.0 mL,7.0 mmol) was added to a suspension of 9H-pyrido[2,3-b]indole-4-carbonitrile (0.422 g, 2.18 mmol) in tetrahydrofuran (12.0 mL,148 mmol) at room temperature under an atmosphere of nitrogen.Additional lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 7 mL)was added at 48 h to drive the reaction to completion. After stirring atotal of 72 h, the mixture was diluted with water (50 mL) and theresultant solids were collected by filtration, washed with water anddried on a Buchner funnel and in vacuo. 9H-Pyrido[2,3-b]indole-4-carboxamidine was isolated as beige solids (0.297 g, 65% yield)and was used without further purification. LCMS (ESI): 211 (M+H)⁺.1253c) 9H-Pyrido[2,3-b] indole-4-carboxamidine (0.295 g, 1.40 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.806 g, 2.12 mmol),3-cyclopropyl-5-fluoro-isonicotinic acid (0.320 g, 1.76 mmol) andN,N-diisopropylethylamine (0.750 mL, 4.30 mmol) were combined inN,N-dimethylformamide (8.0 mL) and stirred for 90 min. The mixture waspoured into ethyl acetate (50 mL) and washed with water (2×5 mL). Thecombined aqueous wash was extracted with ethyl acetate (3×15 mL) whichwas combined with the first organic extract, washed with brine (30 mL),dried over sodium sulfate, filtered and concentrated in vacuo. The crude3-cyclopropyl-5-fluoro-N-[imino-(9H-pyrido[2,3-b]indol-4-yl)-methyl]-isonicotinamide was combined with cesium carbonate(0.914 g, 2.81 mmol) in N,N-dimethylformamide (14.0 mL) and was heatedat 90 OC under an atmosphere of nitrogen overnight. The mixture wasconcentrated in vacuo onto silica gel (4.5 g) then purified (silica gel40 g, 0-10% MeOH:DCM) to afford 5-cyclopropyl-2-(9H-pyrido[2,3-b]indol-4-yl)-3H-pyrido[3,4-d]pyrimidin-4-one (0.230 g; Yield=46.4%). LCMS(ESI): 354 (M+H)⁺.

1253d) 5-Cyclopropyl-2-(9H-pyrido[2,3-b]indol-4-yl)-3H-pyrido[3,4-d]pyrimidin-4-one (18 mg, 0.051 mmol),2,4,6-triisopropylbenzenesulfonyl chloride (17.5 mg, 0.0578 mmol),4-dimethylaminopyridine (1.0 mg, 0.0082 mmol) and triethylamine (35.0 L,0.251 mmol) in N,N-dimethylformamide (1.00 mL) was stirred under anatmosphere of nitrogen at room temperature for 1 h, then a solution ofpiperazine (74.0 mg, 0.859 mmol) in N,N-dimethylformamide (1.0 mL) wasadded and stirring was continued for 3 h. The mixture was concentratedin vacuo and purified by preparative HPLC (0-45% acetonitrile:water,0.1% trifluoracetic acid) to afford4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-9H-pyrido[2,3-b]indole trifluoroacetic acid salt (10.0 mg; Yield=37%;) as a yellowlyophilate. LCMS (ESI): 422 (M+H); ¹H-NMR (DMSO-d6, 400 MHz): δ 12.08(s, 1H), 9.17 (s, 1H), 8.83 (br s, 1H), 8.68 (d, 1H, J=8.4 Hz), 8.59 (d,1H, J=5.1 Hz), 8.26 (s, 1H), 7.89 (d, 1H, J=5.1 Hz), 7.55 (d, 1H, J=7.9Hz), 7.49 (m, 1H), 7.18 (m, 1H), 3.68 (br s, 4H), 3.34 (br s, 4H), 2.77(m, 1H), 1.30 (m, 2H), 1.14 (m, 2H).

Example 1254 1-[5-cyclopropyl-2-(9H-pyrido[2,3-b]indol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol trifluoroaceticacid salt

Analogous to Example 1253d, 5-cyclopropyl-2-(9H-pyrido[2,3-b]indol-4-yl)-3H-pyrido[3,4-d]pyrimidin-4-one (44.0 mg, 0.124 mmol) wasreacted with piperidin-4-ol (34.0 mg, 0.336 mmol) to afford1-[5-cyclopropyl-2-(9H-pyrido[2,3-b]indol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol trifluoroaceticacid salt (32 mg; Yield=47%) as a yellow lyophilate. LCMS (ESI): 437(M+H); ¹H-NMR (DMSO-d₆, 400 MHz): δ 12.12 (s, 1H), 9.07 (s, 1H), 8.60(d, 1H, J=5.0 Hz) 8.54 (d, 1H, J=8.1 Hz), 8.22 (s, 1H), 7.84 (d, 1H,J=5.0 Hz), 7.56 (d, 1H, J=8.0 Hz), 7.49 (m, 1H), 7.17 (m, 1H), 4.11 (m,3H), 3.58 (br s, 2H), 2.61 (m, 1H), 1.89 (m, 2H), 1.55 (m, 2H), 1.92 (m,2H), 1.21 (m, 2H).

Example 12554-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-9H-pyrido[2,3-b]indole trifluoroacetic acid salt

Analogous to Example 1253d,5-cyclopropyl-2-(9H-pyrido[2,3-b]indol-4-yl)-3H-pyrido[3,4-d]pyrimidin-4-one(52.5 mg, 0.148 mmol) was reacted with 2,2-dimethylpiperazine (31.4 mg,0.275 mmol) to afford4-[5-cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-9H-pyrido[2,3-b]indoletrifluoroacetic acid salt (17.5 mg; Yield=21%) as a yellow lyophilate.LCMS (ESI): 450 (M+H); ¹H-NMR (DMSO-d6, 400 MHz): δ 12.09 (s, 1H), 9.17(s, 1H), 9.05 (br s, 2H), 8.67 (d, 1H, J=8.1 Hz), 8.60 (d, 1H, J=5.1Hz), 8.29 (s, 1H), 7.93 (d, 1H, J=5.1 Hz) 7.55 (d, 1H, J=7.9 Hz), 7.49(m, 1H), 7.18 (m, 1H), 3.93 (m, 4H), 3.39 (m, 2H), 2.61 (m, 1H),1.01-1.48 (m, 10H).

The following compounds were synthesized according to the generalsyntheses shown in any of the Scheme(s) provided above using analogousprocedures, starting materials and intermediates.

Analysis Ex Structure Scheme LCMS ¹H-NMR Name 2001

[D4], [D3] Method 5: RT: 3.66 min, MI: 442 [M + H] (400 MHz, d6-DMSO,90° C.) 11.32 (1H, s), 9.03 (1H, s), 8.27 (1H, d, J = 5.1 Hz), 8.11 (1H,s), 8.04 (1H, d, J = 5.1 Hz), 7.21 (1H, d, J = 2.2 Hz), 4.21-4.16 (2H,m), 3.23-3.16 (1H, m), 3.06- 3.01 (1H, m), 2.94-2.82 (3H, m), 2.74-7.66(1H, m), 1.28-1.23 (2H, m), 1.07 (3H, d, J = 6.0 Hz), 1.02-0.98 (2H, m).2-(2-tert-Butyl-1H- pyrrolo[2,3-b]pyridin- 4-yl)-5-cyclopropyl-4-((S)-3- methyl-piperazin-1-yl)- pyrido[3,4-d]pyrimidine2002

[D4], [D3] Method 5: RT: 3.75 min, MI: 456 [M + H] (400 MHz, d6-DMSO,90° C.) 11.38 (1H, br s), 9.11 (1H, s), 8.30 (1H, d, J = 5.0 Hz), 8.21(1H, s), 8.07 (1H, d, J = 5.0 Hz), 7.19 (1H, d, J = 2.3 Hz) 3.97-3.94(2H, m), 3.89 (2H, s), 3.35-3.32 (2H, m), 2.67-2.60 (1H, m), 1.31-1.26(8 H, m), 1.05-1.00 (2H, m). 2-(2-tert-Butyl-1H- pyrrolo[2,3-b]pyridin-4-yl)- 5-cyclopropyl-4-(3,3- dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine 2003

[B4] Method 5: RT: 3.05 min, MI: 495.42 [M + H] (500 MHz, DMSO) 9.06(1H, s), 8.37 (1H, d), 8.17 (1H, s), 7.98 (1H, s), 7.82 (1H, s), 7.80(1H, s), 7.76 (1H, dd), 7.38 (2H, d), 3.92 (4H, s, br), 3.32 (4H, s,br), 2.97 (6H, s), 2.70-2.66 (1H, m), 1.26-1.24 (2H, m), 1.08-1.07 (2H,m). 4-[4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido [3,4-d]pyrimidin-2-yl)-pyridin-2- ylamino]-N,N-dimethyl- benzamide 2004

[B4] Method 5: RT: 2.74 min, MI: 493 [M + H] (DMSO, 500 MHz) 10.13 (1H,s), 9.07 (1H, s), 8.93 (2H, s), 8.48 (1H, s), 8.19 (1H, s), 8.02 (1H,s), 7.02 (1H, m), 4.34 (2H, m), 3.72 (1H, m), 3.48 (4H, m), 3.09 (1H,m), 1.25 (5H, m), 1.09 (2H, m). {4-[5-Cyclopropyl- 4-((S)-3-methyl-piperaizn-1-yl)- pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,4,6- trifluoro-pyridin-2-yl)- amine 2005

[B4] LCMS: Purity: 90% RT: min, MI: 540.289 978 (CDCl₃): 9.06 (s, 1H),8.31 (br d, J = 4.4 Hz, 1H), 8.03 (br s, 2H), 7.76 (dd, J = 5.3; 1.3 Hz,1H), 7.06 (app t, J = 2.0 Hz, 1H), 6.91 (br s, 2H), 6.65 (dd, J = 8.2;2.0 Hz, 1H), 4.59-3.90 (br m, 4H), 3.89-3.84 (m, 4H), 3.84- 3.51 (br s,2H), 3.22-3.16 (m, 4H), 2.62-2.51 (m, 1H), 1.90-1.50 (br m, 3H), 1.27-1.21 (m, 2H), 0.99-0.95 (m, 2H) (+/−)-cis-1-{5- Cyclopropyl-2-[2-(3-morpholin-4-yl- phenylamino)-pyridin- 4-yl]-pyrido[3,4-d]pyrimidin-4- yl}-piperidine-3,4-diol 2006

[B4] LCMS: Purity: 92% RT: min, MI: 444.28 (M + H) (dmso-d6) 9.08 (br s,2H), 8.83 (br s, 1H), 8.81 (s, 1H), 8.00 (s, 1H), 7.83 (br s, 1H), 7.77(d, J = 6.7 Hz, 1H), 7.47 (dd, J = 6.7; 1.5 Hz, 1H), 5.98 (br s, exch.H's), 3.69 (br s, 4H), 3.26 (br s, 1H), 3.09 (br s, 2H), 2.25- 2.17 (m,1H), 1.12 (br s, 2H), 1.05 (d, J = 6.4 Hz, 3H), 1.05-0.95 (m, 4H),0.94-0.70 (m, 5H), 0.40- 0.35 (m, 3H), 0.05-(−0.03) (m, 1H).{4-[5-Cyclopropyl- 4-(3,3- dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2- yl]-pyridin-2-yl}-((R)-1-cyclopropyl-ethyl)-amine 2007

[B4] LCMS: Purity: 94%, RT: min, MI: 480.28 (M + H) (dmso-d6) 9.39 (brs, 3H), 9.09 (s, 1H), 8.28 (s, 1H), 8.13 (d, J = 6.5 Hz, 1H), 8.10 (brs, 1H), 7.79 (d, J = 6.5 Hz, 1H), 7.51 (d, J = 7.4 Hz, 2H), 7.44 (app t,J = 7.4 Hz, 2H), 7.33 (app t, J = 7.4 Hz, 1H), 5.17 (br s, 1H),4.20-3.80 (m, 4H), 3.38 (br s, 2H), 2.52-2.47 (m, 1H), 1.63 (d, J = 6.7Hz, 3H), 1.60-1.00 (m, 10H) {4-[5-Cyclopropyl- 4-(3,3-dimethyl-piperazin-1-yl)- pyrido[3,4-d[pyrimidin- 2-yl]-pyridin-2-yl}-((R)-1-phenyl- ethyl)-amine 2008

[D4], [D3] Method 5: RT: 3.98 min, MI: 456.43 [M + H] (d6-DMSO, 400 MHz,90° C.) 11.34 (1H, s), 9.11 (1H, s), 8.67 (1H, s), 8.28 (1H, d), 8.05(1H, d), 7.20 (1H, s), 4.36 (1H, m), 3.98 (2H, m), 3.10 (1H, m), 3.02(2H, m), 2.96 (2H, m), 2.54 (2H, s), 2.22 (2H, m), 2.17 (1H, m), 1.97(1H, m), 1.47 (9H, s), 1.07 (3H, d). 2-(2-tert-Butyl-1H-pyrrolo[2,3-b]pyridin- 4-yl)- 5-cyclobutyl-4-((S)-3-methyl-piperazin-1-yl)- pyrido[3,4-d]pyrimidine 2009

[D4], [D3] Method 5: RT: 3.99 min, MI: 506 [M + H] (400 MHz, d6-DMSO,90° C.) 11.18 (1H, br s), 8.90 (1H, s), 8.25 (1H, d, J = 5.1 Hz), 8.08(1H, s), 8.04 (1H, d, J = 5.1 Hz), 7.61 (1H, dt, J = 7.7, 1.8 Hz),7.43-7.38 (1H, m), 7.25 (1H, dt, J = 7.5, 1.2 Hz), 7.21-7.16 (1H, m),6.88 (1H, s), 3.60- 3.57 (4H, m), 2.89-2.86 (4H, m), 2.68-2.64 (1H, m),1.69-1.66 (2H, m), 1.40-1.37 (2H, m), 1.26- 1.21 (2H, m), 0.98-0.955-Cyclopropyl-2-{2-[1- (2-fluoro-phenyl)- cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-4- yl}-4-piperazin-1-yl- pyrido[3,4-d]pyrimidine(2H, m). 2010

[D4], [D3] Method 5: RT: 3.90 min, MI: 442.48 [M + H] (d6-DMSO, 500 MHz)11.71 (1H, s), 9.07 (1H, s), 8.65 (1H, s), 8.26 (1H, d), 8.04 (1H, d),7.17 (1H, s), 4.24 (1H, m), 3.84 (1H, m), 3.56 (1H, m), 3.38 (1H, m),3.36 (1H, m), 2.94 (2H, s), 2.41 (2H, m), 2.15 (2H, m), 2.12 (1H, m),2.04 (1H, m), 1.41 (9H, s), 1.10 (3H, s), 0.75 (3H, s).2-(2-tert-Butyl-1H- pyrrolo[2,3-b]pyridin- 4-yl)-5-cyclobutyl-4-piperazin-1-yl- pyrido[3,4-d]pyrimidine 2011

[B4] LCMS: Purity: 97%, RT: min, MI: 475.19 (MH)+, (400 MHz, d6-DMSO,δ): 10.45 (s, 1H), 9.15 (s, 1H), 8.90-8.75 (m, 3H), 8.62 (s, 1H), 8.47(d, J = 5.3 Hz, 1H), 7.92 (dd, J = 5.2, 1.3 Hz, 1H), 7.80 (dd, J = 11.2,1.6 Hz, 1H), 6.69 (dt, J = 8.5, 1.6 Hz, 1H), 4.25 (pent, J = 8.8 Hz,1H), 3.89-3.84 (m, 4H), 3.40-3.17 (m, 4H), 2.52- 2.42 (m, 2H), 2.28-2.03(m, 3H), 1.97-1.87 (m, 1H). [4-(5-Cyclobutyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]- (4,6-difluoro-pyridin-2-yl)-amine 2012

[B4] LCMS: Purity: 96%, RT: min, MI: 505.25 (MH)+ (400 MHz, d6-DMSO, δ):10.63 (br s, 1H), 9.15 (s, 1H), 9.12 (s, 1H), 8.89 (br s, 2H), 8.68 (s,1H), 8.45 (d, J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.94 (dd, J = 5.4, 1.3 Hz,1H), 7.60 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 9.2, 1.7 Hz, 1H), 3.96 (brs, 4H), 3.36 (br s, 4H), 2.76-2.68 (m, 1H), 2.12- 2.05 (m, 1H),1.30-1.24 (m, 2H), 1.12-1.07 (m ,2H), 1.04-0.98 (m, 2H), 0.85- 0.80 (m,2H). [4-(5-Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-yl]-(6-cyclopropyl- [1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine 2013

[B4] LCMS: Purity: 97%, RT: min, MI: 497.24 (MH)+ (400 MHz, d6-DMSO, δ):10.26 (br s, 1H), 9.10 (s, 1H), 8.90 (br s, 2H), 8.83 (s, 1H), 8.44 (d,J = 5.7 Hz, 1H), 8.22 (s, 1H), 8.07 (d, J = 1.5 Hz, 1H), 8.01 (d, J =5.6 Hz, 1H), 7.83 (d, J = 11.2 Hz, 1H), 3.94 (br s, 4H), 3.61 (pent, J =8.7 Hz, 1H), 3.34 (br s, 4H), 2.72-2.65 (m, 1H), 2.37-2.28 (m, 2H),2.22-2.11 (m, 2H), 2.08- 1.95 (m, 1H), 1.91-1.82 (m, 1H), 1.30-1.24 (m,2H), 1.12-1.07 (m, 2H). (5-Cyclobutyl-3-fluoro- pyridin-2-yl)-[4-(5-cyclopropyl-4-piperazin- 1-yl-pyrido[3,4-d] pyrimidin-2-yl)-pyridin-2-yl]-amine 2014

[B4] LCMS: Purity: >95%, RT: min, MI: 507 (M + H) 1H-NMR DMSO 9.69 (brs, 1H), 8.93 (s, 1H), 8.60 (s, 1H), 8.40 (m, 1H), 8.27 (m, 1H), 8.12 (s,1H), 7.91 (m, 1H), 4.62 (br m, 1H), 3.13 (s, 3H), 3.08 (m, 2H), 2.66 (m,2H), 2.43 (m, 1H), 1.79 (br m, 4H), 1.22 (m, 3H), 0.96 (m, 2H){5-Cyclopropyl-2-[2- (3,5,6-trifluoro- pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}- methyl-piperidin-4-yl-amine 2015

[B4] LCMS: Purity: 95%, RT: min, MI: 476.21 (M + H) (dmso-d6) 9.91 (brs, 1H), 9.13 (br s, 1H), 9.10 (s, 2H), 8.38-8.32 (m, 2H), 8.24 (s, 1H),8.15 (s, 1H), 7.90 (dd, J = 5.8; 1.1 Hz, 1H), 5.25 (br s, exch. H's),4.19 (q, J = 7.2 Hz, 2H), 3.96 (br s, 4H), 3.67 (br s, 4H), 2.90-2.60(m, 1H), 1.47 (t, J = 7.2 Hz, 3H), 1.34-1.25 (m, 2H), 1.41-1.08 (m, 2H)(4-Chloro-1-ethyl-1H- pyrazol-3-yl)-[4-(5- cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-amine 2016

[B4] LCMS: Purity: 96%, RT: min, MI: 496.20 (M + H) (dmso-d6) 10.68 (brs, 1H), 9.09 (br s, 3H), 8.44 (s, 1H), 8.38 (d, J = 5.8 Hz, 1H), 8.22(s, 1H), 7.87 (d, J = 5.5 Hz, 2H), 6.50 (d, J = 2.4 Hz, 1H), 5.86 (br s,exch. H's), 5.12 (q, J (CH2—CF3) = 9.0 Hz, 2H), 3.96 (br s, 4H), 3.35(br s, 4H), 2.73-2.65 (m, 1H), 1.32-1.23 (m, 2H), 1.14-1.06 (m, 2H)[4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido [3,4-d]pyrimidin-2-yl)-pyridin-2-yl]- [1-(2,2,2-trifluoro-ethyl)- 1H-pyrazol-3-yl]-amine2017

[B4] LCMS: Purity: 95%, RT: min, MI: 524.24 (M + H) (dmso-d6) 10.79 (brs, 1H), 9.32 (br s, 2H), 9.10 (s, 1H), 8.42-8.36 (m, 2H), 8.26 (s, 1H),7.93-7.87 (m, 2H), 6.58 (d, J = 2.3 Hz, 1H), 5.56 (br s, exch. H's),5.14 (q, J(CH2CF3) = 9.0 Hz, 2H), 3.99 (br s, 4H), 3.38 (br s, 2H),2.58-2.50 (m, overlapping solvent signal, 1H), 1.70-1.00 (m, 10H){4-[5-Cyclopropyl- 4-(3,3- dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2- yl]-pyridin-2-yl}- [1-(2,2,2-trifluoro-ethyl)-1H-pyrazol- 3-yl]-amine 2018

[B4] LCMS: Purity: 97%, RT: min, MI: 484.28 (M + H) (dmso-d6) 11.37 (brs, 1H), 9.34 (br s, 2H), 9.10 (s, 1H), 8.44 (d, J = 6.3 Hz, 1H), 8.42(s, 1H), 8.28 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.88 (d, J = 2.2 Hz,1H), 6.32 (d, J = 2.3 Hz, 1H), 4.94 (br s, exch. H's), 4.59 (hept, J =6.6 Hz, 1H), 3.99 (br s, 4H), 3.38 (br s, 2H), 2.55-2.48 (m, partiallyoverlaped by solvent peak, 1H), 1.53 (d, J = 6.6 Hz, 6H), 1.52-1.00 (m,10H) {4-[5-Cyclopropyl- 4-(3,3- dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin- 2-yl]-pyridin- 2-yl}-(1-isopropyl-1H-pyrazol-3-yl)-amine 2019

[B4] LCMS: Purity 92%, RT: min, MI: 507 (M + H) 1H-NMR: DMSO 10.03 (brs, 1H), 8.93 (s, 1H), 8.73 (s, 1H), 8.45 (m, 1H), 8.12 (s, 1H), 7.97 (m,1H), 7.01 (m, 1H), 4.59 (br m, 1H), 3.12 (s, 3H), 3.00 (m, 2H), 2.67 (m,2H), 2.42 (m, 1H), 1.72 (br m, 4H), 1.23 (m, 3H), 0.96 (m, 2H){5-Cyclopropyl-2-[2- (3,4,6-trifluoro-pyridin-2- ylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-methyl- piperidin-4-yl-amine2020

[B4] LCMS: Purity: 95%, RT: min, MI: 479 (M + H): 1H-NMR: DMSO 9.66 (brs, 1H), 9.02 (s, 1H), 8.75 (s, 1H), 8.45 (s, 1H), 8.39 (m, 1H), 8.26 (m,1H), 7.95 (m, 2H), 4.85 (m, 1H), 3.20 (m, 1H), 3.04 (m, 1H), 2.95 (m,1H), 2.87 (m, 1H), 2.56 (m, 1H), 2.26 (m, 1H), 1.85 (m, 1H), 1.19 (m,3H), 1.08 (m, 2H) {5-Cyclopropyl-2-[2- (3,5,6-trifluoro-pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-pyrrolidin-3-yl-amine 2021

[B4] LCMS: Purity: >95%, RT: min, MI: 479 (M + H) 1H-NMR: DMSO 10.07 (s,1H), 9.08 (s, 1H), 9.03 (br s, 1H), 8.95 (br s, 1H), 8.82 (s, 1H), 8.48(m, 2H), 8.03 (m, 1H), 7.89 (m, 1H), 7.00 (m, 1H), 5.03 (m, 1H), 3.69(m, 1H), 3.48 (m, 2H), 3.34 (m, 1H), 2.62 (m, 1H), 2.52 (m, 2H), 2.26(m, 1H), 1.22 (m, 2H), 1.07 (m, 2H) {5-Cyclopropyl-2-[2-(3,4,6-trifluoro- pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}- pyrrolidin-3-yl-amine 2022

[B4] LCMS: Purity: 95%, RT: min, MI: 479.25 (MH)+ (400 MHz, d6-DMSO, δ):10.50 (br s, 1H), 9.22 (s, 1H), 9.18 (s, 1H), 8.95-8.75 (m, 4H), 8.44(d, J = 5.3 Hz, 1H), 7.91 (dd, J = 5.4, 1.4 Hz, 1H), 7.71-7.63 (m, 2H),7.14 (dt, J = 6.5, 2.0 Hz, 1H), 4.32-4.23 (m, 1H), 3.87 (br s, 4H),3.41-3.23 (m, 4H), 2.51-2.43 (m, 2H), 2.29- 2.05 (m, 3H), 1.98-1.88 (m,1H). [4-(5-Cyclobutyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine 2023

[B4] LCMS: Purity: 93%, RT: min, MI: 509.3 (M + H) (dmso-d6) 9.93 (br s,1H), 9.50-8.5 (broad signal - in the noise), 9.12 (br s, 1H), 9.11 (s,1H), 8.29 (d, J = 5.8 Hz, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.80 (dd, J =5.8; 1.3 Hz, 1H), 7.33 (br s, 1H), 7.28 (qpp t, J = 8.1 Hz, 1H), 7.15(d, J = 8.1 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 3.97 (br s, 4H),3.82-3.78 (m, 4H), 3.37 (br s, 4H), 3.21-3.16 (m, 4H), 2.75- 2.68 (m,1H), 1.33-1.26 (m, [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-yl]-(3-morpholin-4-yl- phenyl)-amine 2H),1.16-1.10 (m, 2H) 2024

[D4], [D3] Method 5: RT: 3.93 min, MI: 455.38 [M + H] (500 MHz, DMSO)13.20 (1H, s), 8.99 (1H, s, br), 8.88 (1H, s, br), 8.81 (1H, s), 8.69(1H, d), 8.25 (1H, d), 7.95 (1H, s), 4.30-4.24 (1H, 3.86-3.81 (4H, m),3.35-3.29 (4H, m), 2.50.2.45 (2H, m), 2.26-2.08 (3H, m), 1.96-1.90 (1H,m). 5-Cyclobutyl-4- piperazin-1-yl-2- (2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4- yl)-pyrido[3,4-d] pyrimidine 2025

[B4] LCMS: Purity: >95%, RT: min, MI: 474 (M + H) 1H-NMR: DMSO 9.02 (s,1H), 8.93 (br m, 2H), 8.89 (s, 1H), 8.21 (m, 2H), 7.84 (s, 1H), 7.71 (m,1H), 7.29 (m, 1H), 7.16 (m, 2H), 5.13 (br m, 1H), 3.79 (m, 1H), 3.45 (m,1H), 3.29 (br m, 2H), 3.12 (s, 3H), 2.54 (m, 1H), 2.40 (m, 1H), 2.25 (brm, 1H), 1.26 (br m, 2H), 1.01 (m, 2H) {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)- pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl- pyrrolidin-3-yl-amine 2026

[B4] LCMS: Purity: >95%, RT: min, MI: 446 (M + H) 1H-NMR: DMSO 9.07 (s,1H), 8.90 (br s, 3H), 8.51 (s, 1H), 8.25 (d, 1H, J = 4.6 Hz), 8.17 (d,1H, J = 5.6 Hz), 7.78 (s, 1H), 7.66 (m, 1H), 7.30 (m, 1H), 7.18 (m, 2H),5.11 (m, 1H), 4.44 (m, 2H), 4.25 (m, 2H), 2.64 (m, 1H), 2.54 (m, 1H),1.27 (m, 2H), 1.05 (m, 2H) Azetidin-3-yl-{5- cyclopropyl-2-[2-(2,6-difluoro-phenylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-amine2027

[D3] LCMS: Purity: 95%, RT: min, MI: 458 (M + H)+ 1H-NMR (DMSO-d6, 400MHz): 9.05 (s, 1H), 8.85 (br s, 2H), 8.69 (d, 1H, J = 4.1 Hz), 8.24 (s,1H), 7.53 (d, 1H, J = 4.9 Hz), 7.34 (m, 1H), 6.78 (m, 1H), 3.73 (m, 4H),3.25 (m, 4H), 2.77 (m, 1H), 1.29 (m, 2H), 1.14 (m, 2H)4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)-5,8-difluoro-9H-pyrido[2,3- b]indole 2028

[D4], [D3] Method 5: RT: 4.03 min, MI: 470.45 [M + H] (d6-DMSO, 500 MHz)11.71 (1H, s), 9.07 (1H, s), 8.65 (1H, s), 8.26 (1H, d), 8.04 (1H, d),7.17 (1H, s), 4.24 (1H, m), 3.84 (1H, m), 3.56 (1H, m), 3.38 (1H, m),3.36 (1H, m), 2.94 (2H, s), 2.41 (2H, m), 2.15 (2H, m), 2.12 (1H, m),2.04 (1H, m), 1.41 (9H, s), 1.10 (3H, s), 0.75 (3H, s).2-(2-tert-Butyl-1H- pyrrolo[2,3-b]pyridin-4- yl)-5-cyclobutyl-4-(3,3-dimethyl-piperazin-1-yl)- pyrido[3,4-d]pyrimidine 2029

[B4] LCMS: Purity: >90%, RT: min, MI: 460 (M + H) (d6-DMSO) 9.04 (s,1H), 8.88 (s, 1H), 8.85 (br s, 2H), 8.24 (s, 1H), 8.19 (d, 1H, J = 5.3Hz), 7.73 (s, 1H), 7.61 (m, 1H), 7.29 (m, 1H), 7.18 (m, 2H), 4.74 (m,1H), 4.24-4.35 (br m, 4H), 3.11 (s, 3H), 2.70 (m, 1H), 1.30 (br m, 2H),1.07 (m, 2H) Azetidin-3-yl-{5- cyclopropyl-2-[2-(2,6-difluoro-phenylamino)- pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl- amine 2030

[B4] LCMS: Purity: 96%, RT: min, MI: 530.15 (M + H) (dmso-d6) 9.36 (brs, 1H), 9.09 (s, 1H), 9.02 (br s, 2H), 8.35 (d, J = 5.4 Hz, 1H), 8.27(s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.85 (d, J = 5.4 Hz, 1H), 5.16 (q,J(H, F) = 9.0 Hz, 2H), 3.94 (br s, 4H), 3.36 (br s, 4H), 2.77-2.66 (m,1H), 1.33-1.25 (m ,2H), 1.15-1.07 (m, 2H) [4-Chloro-1-(2,2,2-trifluoro-ethyl)-1H- pyrazol-3-yl]-[4-(5- cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d] pyrimidin-2-yl)-pyridin- 2-yl]-amine 2031

[D3] LCMS: Purity: 95%, RT: min, MI: 440 (M + H)+ 1H-NMR (DMSO-d6, 400MHz): 12.60 (s, 1H), 9.18 (s, 1H), 8.88 (br s, 2H), 8.66 (d, 1H, J = 5.1Hz), 8.53 (d, 1H, J = 8.1 Hz), 8.27 (s, 1H), 7.95 (d, 1H, J = 5.1 Hz),7.38 (m, 1H), 7.16 (ddd, 1H, J = 5.1, 8.1, 8.1 Hz), 3.92 (br s, 4H),3.34 (br s, 4H), 2.76 (m, 1H), 1.30 (m, 2H), 1.14 (m, 2H)4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)-8-fluoro-9H-pyrido [2,3-b]indole 2032

[B4] LCMS: Purity: 99%, RT: min, MI: 483.21 (MH)+ (400 MHz, d6-DMSO, δ):10.62 (s, 1H), 9.27 (s, 1H), 9.13 (s, 1H), 8.90 (br s, 2H), 8.76 (dd, J= 6.7, 0.7 Hz, 1H), 8.46 (dd, J = 5.2, 0.4 Hz, 1H), 8.20 (s, 1H), 7.94(dd, J = 5.2, 1.4 Hz, 1H), 7.65- 7.59 (m, 1H), 7.14-7.08 (m, 1H), 3.97(br s, 4H), 3.36 (br s, 4H), 2.75-2.68 (m, 1H), 1.30-1.24 (m, 2H),1.12-1.07 (m, 2H). [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-(8-fluoro- [1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine 2033

[B4] LCMS: Purity: 98%, RT: min, MI: 483.19 (MH)+ (400 MHz, d6-DMSO, δ):10.50 (s, 1H), 9.17 (s, 1H), 9.15 (s, 1H), 8.93 (dd, J = 7.4, 5.5 Hz,1H), 8.87 (br s, 2H), 8.45 (dd, J = 5.2, 0.5 Hz, 1H), 8.21 (s, 1H), 7.92(dd, J = 5.3, 1.4 Hz, 1H), 7.60 (dd, J = 9.4, 2.7 Hz, 1H), 7.15 (dt, J =7.6, 2.8 Hz, 1H), 3.95 (br s, 4H), 3.36 (br s, 4H), 2.75-2.69 (m, 1H),1.30- 1.24 (m, 2H), 1.12-1.07 (m, 2H). [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin- 2-yl]-(7-fluoro-[1,2,4]triazolo[1,5-a] pyridin-2-yl)-amine 2034

[B4] LCMS: Purity: >95%, RT: min, MI: 460 (M + H) 1H-NMR: DMSO 9.07 (s,1H), 9.00 (br s, 2H), 8.90 (s, 1H), 8.50 (s, 1H), 8.19 (d, 1H, J = 4.9Hz), 7.85 (m, 2H), 7.72 (m, 1H), 7.32 (m, 1H), 7.18 (m, 2H), 4.98 (m,1H), 3.70 (m, 1H), 3.45 (m, 2H), 3.37 (m, 1H), 2.62 (m, 1H), 2.45 (m,1H), 2.24 (m, 1H), 1.21 (m, 2H), 1.06 (m, 2H) {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-(S)-pyrrolidin-3-yl-amine 2035

[B4] LCMS: Purity: >95%, RT: min, MI: 460 (M + H) 1H-NMR: DMSO 9.07 (s,1H), 9.01 (br m, 2H), 8.94 (s, 1H), 8.50 (s, 1H), 8.18 (d, 1H, J = 5.2Hz), 7.85 (m, 2H), 7.73 (m, 1H), 7.30 (m, 1H), 7.19 (m, 2H), 4.97 (m,1H), 3.70 (m, 1H), 3.44 (m, 3H), 2.61 (m, 1H), 2.47 (m, 1), 2.24 (m,1H), 1.21 (m, 2H), 1.06 (m, 2H) {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine 2036

[D3] LCMS: Purity: 95%, RT: min, MI: 458 (M + H)+ 1H-NMR (DMSO-d6, 400MHz): 12.84 (s, 1H), 9.20 (s, 1H), 8.87 (br s, 2H), 8.70 (dd, 1H, J =4.4, 8.8 Hz), 8.65 (d, 1H, J = 5.1 Hz), 8.26 (s, 1H), 8.01 (d, 1H, J =5.1 Hz), 7.23 (m, 1H), 3.90 (m, 4H), 3.34 (m, 4H), 2.75 (m, 1H), 1.29(m, 2H), 1.13 (m, 2H) 4-(5-Cyclopropyl-4- piperaizn-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-7,8- difluoro-9H-pyrido[2,3- b]indole 2037

[B4] Method 5: RT: 2.76 min, MI: 507 [M + H] (DMSO, 500 MHz) 10.02 (1H,s), 8.98 (1H, s), 8.89 (1H, m), 8.45 (1H, d), 8.10 (1H, s), 7.98 (1H,s), 7.01 (1H, m), 4.09 (2H, m), 3.04 (2H, m), 2.69 (1H, m), 1.22 (4H,m), 1.06 (6H, m), unidentified 2 × CH protons. Peaks are too broad.{4-[5-Cyclopropyl- 4-((cis)-3,5-dimethyl- piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(3,4,6- trifluoro-pyridin-2-yl)-amine 2038

[B4] LCMS: Purity: 97%, RT: 2.76 min, MI: 507 (MH)+ 1H-NMR: DMSO 9.04(s, 1H), 8.81 (br s, 2H), 8.54 (m, 1H), 8.48 (s, 1H), 8.18 (d, 1H, J =5.2 Hz), 7.78 (s, 1H), 7.72 (m, 2H), 7.29 (m, 1H), 7.18 (m, 2H), 4.71(m, 1H), 3.35 (m, 2H), 2.62 (m, 1H), 2.32 (m, 1H), 2.23 (m, 1H), 1.72(m, 2H), 1.48 (s, 3H), 1.39 (s, 3H), 1.16 (m, 2H), 1.05 (m, 2H){5-Cyclopropyl-2-[2-(2,6- difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-(2,2-dimethyl-piperidin-4-yl)- amine 2039

[B4] LCMS: Purity: 97%, RT: 2.76 min, MI: 507 (MH)+ (400 MHz, d6-DMSO,δ): 10.51 (br s, 1H), 9.23-9.20 (m, 1H), 9.18 (s, 1H), 9.16 (s, 1H),8.86 (br s, 2H), 8.45 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H), 7.92 (d, J =5.2 Hz, 1H), 7.80-7.70 (m, 2H), 3.96 (br s, 4H), 3.36 (br s, 4H), 2.76-2.67 (m, 1H), 1.30-1.24 (m, 2H), 1.12-1.07 (m, 2H). [4-(5-Cyclopropyl--4piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin- 2-yl]-(6-fluoro-[1,2,4]triazolo[1,5-a] pyridin-2-yl)-amine 2040

[B4] LCMS: Purity: 97%, RT: 2.76 min, MI: 507 (MH)+ (400 MHz, d6-DMSO,δ): 10.61 (s, 1H), 9.24 (s, 1H), 9.20-9.17 (m, 1H), 9.14 (s, 1H), 8.87(br s, 2H), 8.46 (dd, J = 5.1, 0.6 Hz, 1H), 8.20 (s, 1H), 8.04-7.97 (m,1H), 7.93 (dd, J = 5.2, 1.4 Hz, 1H), 3.96 (br s, 4H), 3.35 (br s, 4H),2.75-2.67 (m, 1H), 1.30-1.24 (m, 2H), 1.12- 1.07 (m, 2H).[4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-yl]-6,8-difluoro- [1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine 2041

[B4] LCMS: Purity: 97%, RT: 2.76 min, MI: 507 (MH)+ (400 MHz, d6-DMSO,δ): 10.61 (s, 1H), 9.31 (s, 1H), 9.10 (s, 1H), 8.90 (br s, 2H), 8.46 (d,J = 5.3 Hz, 1H), 8.20 (s, 1H), 7.95 (dd, J = 5.2, 1.3 Hz, 1H), 7.77-7.70(m, 1H), 7.56 (dd, J = 8.8, 0.6 Hz, 1H), 7.10-7.05 (m ,1H), 3.97 (br s,4H), 3.36 (br s, 4H), 2.76-2.67 (m, 1H), 1.30-1.24 (m, 2H), 1.12-1.07(m, 2H). [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-yl]-(5-fluoro- [1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine 2042

[B4] LCMS: Purity: 97%, RT: 2.76 min, MI: 507 (MH)+ (dmso-d6) 9.17 (s,1H), 9.10 (br s, 3H), 8.86 (s, 1H), 8.12 (d, J = 6.3 Hz, 1H), 7.99 (brs, 1H), 7.69 (d, J = 6.3 Hz, 1H), 7.50 (app d, J = 7.3 Hz, 2H), 7.42(app t, J = 7.3 Hz, 2H), 7.32 (app t, J = 7.3 Hz, 1H), 5.17-5.12 (m,1H), 4.32-4.20 (m, 1H), 3.90- 3.78 (m, 4H), 3.38 (br s, 2H), 3.26 (br s,2H), 2.51- 2.44 (m, 2H), 2.35-2.05 (m, 3H), 2.00-1.92 (m, 1H), 1.60 (d,J = 6.8 Hz, 3H) [4-(5-Cyclobutyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-((R)-1- phenyl-ethyl)-amine 2043

[B4] LCMS: Purity: 97%, RT: 2.76 min, MI: 507 (MH)+ (dmso-d6) 9.83 (brs, 1H), 9.26 (br s, 2H), 9.08 (s, 1H), 8.34 (d, J = 5.8 Hz, 1H), 8.26(s, 1H), 8.23 (br s, 1H), 8.15 (s, 1H), 7.90 (d, J = 5.8 Hz, 1H), 4.18(q, J = 7.2 Hz, 2H), 3.96 (br s, 4H), 3.38 (br s, 2H), 2.58-2.49 (m,overlapped w/ solvent signals, 1H), 1.47 (t, J = 7.2 Hz, 3H), 1.49-1.06(m, 10H) (4-Chloro-1-ethyl-1H- pyrazol-3-yl)-{4-[5- cyclopropyl-4-(3,3-dimethyl-piperazin- 1-yl)-pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2-yl}-amine 2044

[B4] LCMS: Purity: 97%, RT: 2.76 min, MI: 507 (MH)+ (400 MHz, d6-DMSO,δ): 11.50 (br s, 1H), 9.38 (s, 1H), 9.14 (s, 1H), 8.87 (br s, 2H), 8.53(d, J = 5.3 Hz, 1H), 8.21 (s, 1H), 8.03 (dd, J = 5.2, 1.4 Hz, 1H), 7.59-7.55 (m, 2H), 7.30 (dt, J = 7.6, 1.1 Hz, 1H), 7.21 (dt, J = 7.8, 1.1 Hz,1H), 3.98 (br s, 4H), 3.38 (br s, 4H), 2.76- 2.68 (m ,1H), 1.30-1.24 (m,2H), 1.12-1.07 (m, 2H). Benzooxazol-2-yl-[4-(5- cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-amine 2045

[B4] LCMS: Purity: 97%, RT: 2.76 min, MI: 507 (MH)+ (400 MHz, d6-DMSO,δ): 11.75 (br s, 1H), 9.10 (s, 1H), 8.86 (br s, 2H), 8.55 (d, J = 5.8Hz, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.97 (dd, J = 5.3, 1.4 Hz, 1H),7.92 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.42-7.37 (m, 1H),7.25-7.20 (m, 1H), 3.95 (br s, 4H), 3.34 (br s, 4H), 2.73-2.65 (m, 1H),1.29-1.24 (m, 2H), 1.12- 1.06 (m, 2H). Benzothiazol-2-yl-[4-(5-cyclopropyl-4-piperazin- 1-yl-pyrido [3,4-d][primidin-2-yl)-pyridin-2-yl]-amine 2046

[B4] LCMS: Purity: 97%, RT: 2.76 min, MI: 507 (MH)+ (400 MHz, d6-DMSO,δ): 13.68 (br s, 1H), 11.71 (br s, 1 H), 9.10 (s, 1H), 8.93 (br s, 2H),8.75-8.62 (m, 1H), 8.60-8.45 (m, 1H), 8.27- 8.20 (m, 2H), 7.85-7.65 (m,2H), 4.15-3.80 (m, 7H), 3.35 (m ,4H), 2.73-2.65 (m, 1H), 1.30-1.24 (m,2H), 1.13-1.07 (m, 2H). [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-yl]-(1-methyl-1H- benzoimidazol-2-yl)-amine 2047

[B4] Method 5: RT: 2.77 min, MI: 501 [M + H] (DMSO, 400 MHz, 90° C.)8.98 (1H, s), 8.85 (1H, s), 8.38 (1H, d), 8.13 (1H, s), 7.91 (1H, dd),7.46 (1H, m), 3.77 (4H, t), 2.91 (4H, t), 2.66 (1H, m), 1.96 (1H, m),1.27 (2H, m), 0.98 (4H, m), 0.79 (2H, m). (5-Cyclopropyl-3,6-difluoro-pyridin-2-yl)- [4-(5-cyclopropyl- 4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-amine 2048

[D4], [D3] Method 5: RT: 3.03 min, MI: 506 [M + H] (400 MHz, d6-DMSO,90° C.) 11.30 (1H, s), 8.96 (1H, s), 8.27 (1H, d, J = 5.0 Hz), 8.09 (1H,s), 8.05 (1H, d, J = 5.0 Hz), 7.50-7.46 (2H, m), 7.17-7.13 (2H, m), 7.00(1H, s), 3.62 (4H, m), 2.88-2.85 (4H, m), 2.70- 2.67 (1H, m), 1.60-1.57(2H, m), 1.39-1.36 (2H, m), 1.28-1.23 (2H, m), 1.00-0.96 (2H, m).5-Cyclopropyl-2- {2-[1-(4-fluoro-phenyl)- cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-4- yl}-4-piperazin-1-yl- pyrido[3,4-d]pyimidine 2049

[B4] Method 5: RT: 1.68 min, MI: 527 [M + H] (DMSO, 500 MHz) 8.95 (1H,s), 8.11 (1H, d), 8.08 (1H, s), 7.52 (1H, s), 7.40 (1H, d), 6.72 (1H,d), 4.17 (2H, s), 3.76 (1H, m), 3.32 (2H, s), 3.16 (3H, m), 2.91 (3H,m), 2.86 (2H, m), 2.46 (1H, m), 1.90 (2H, m), 1.48 (2H, m), 1.23 (2H,m), 1.10 (2H, m), 1.08 (4H, m). {4-[5-Cyclopropyl- 4-((S)-3-methyl-piperazin-1-yl)-pyrido [3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-[1-(2,2,2-trifluoro-ethyl)-piperidin- 4-yl]-amine 2050

[B4] LCMS: Purity: 100%, RT: 1.68 min, MI: 527 (MH)+ (400 MHz, D6-DMSO,δ): 9.67 (s, 1H), 9.08 (s, 1H), 8.88 (br s, 2H), 8.53 (d, J = 1.6 Hz,1H), 8.44 (d, J = 5.3 Hz, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.86-7.76 (m,4H), 7.67 (dd, J = 8.9, 2.1 Hz, 1H), 7.47-7.42 (m, 1H), 7.36-7.31 (m,1H), 3.93 (br s, 4H), 3.34 (br s, 4H), 2.74-2.66 (m, 1H), 1.29-1.23 (m,2H), 1.12-1.06 (m ,2H). [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-yl]-naphthalen-2-yl- amine 2051

[B4] LCMS: Purity: 100%:, RT: 1.68 min, MI: 527 (MH)+ (400 MHz, d6-DMSO,δ): 9.52 (s, 1H), 9.07 (s, 1H), 8.86 (br s, 2H), 8.37 (d, J = 5.4 Hz,1H), 8.19 (s, 1H), 8.06 (t, J = 1.8 Hz, 1H), 8.00 (s, 1H), 7.78-7.73 (m,2H), 7.67-7.64 (m, 2H), 7.52- 7.47 (m, 2H), 7.42-7.36 (m, 2H), 7.22 (d,J = 7.9 Hz, 1H), 3.94 (br s, 4H), 3.32 (br s, 4H), 2.73-2.65 (m, 1H),1.29-1.23 (m, 2H), 1.11-1.06 (m, 2H). Biphenyl-3-yl-[4-(5-cyclopropyl-4- piperazin-1-yl-pyrido [3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine 2052

[B4] LCMS: Purity: 100%, RT: 1.68 min, MI: 527 (MH)+ (dmso-d6) 9.86 (brs, 1H), 9.57 (br s, 1H), 9.08 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 8.20(s, 1H), 7.97 (s, 1H), 7.72 (br d, J = 5.0 Hz, 1H), 7.44 (s, 1H),7.24-7.21 (m, 2H), 6.70-6.66 (m, 1H), 5.25 (br signal, exchangeableprotons), 4.80-4.20 (m, 2H), 4.20- 3.90 (m, 2H), 3.85-3.79 (m, 2H),3.59-3.54 (m, 2H), 3.40-3.10 (m, 4H), 3.00 (app t, J = 12.5 Hz, 2H),2.90 (s, 3H), 2.70 (br s, 1H), 1.33-1.22 (m, 2H), 1.14- 1.06 (m, 2H){4-[5-Cyclopropyl- 4-((R)-3-trifluoromethyl- piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2- yl]-pyridin-2-yl}-[3-(4-methyl-piperazin-1-yl)- phenyl]-amine 2053

[B4] LCMS: Purity: 100%, RT: 1.68 min, MI: 527 (MH)+ (dmso-d6) 11.25 (brs, 1H), 9.09 (s, 1H), 8.37 (d, J = 6.4 Hz, 1H), 8.34 (s, 1H), 8.21 (s,1H), 7.88 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 6.23 (d, J =2.4 Hz, 1H), 4.70-3.95 (m, 3H), 3.89 (s, 3H), 3.89 (overlapped m, 1H),3.72 (br s, 1H), 3.25 (br s, 3H), 2.73 (br s, 1H), 1.35-1.20 (m, 2H),1.15-1.00 (m, 2H) {4-[5-Cyclopropyl- 4-((R)-3-trifluoromethyl-piperazin-1-yl)- pyrido[3,4-d]pyrimidin-2- yl]-pyridin-2-yl}-(1-methyl-1H-pyrazol-3-yl)- amine 2054

[B4] LCMS: Purity: 95%, MI: 479 (MH)+ 1H-NMR: DMSO 10.08 (s, 1H), 9.08(br s, 2H), 9.00 (br s, 1H), 8.82 (s, 1H), 8.51 (s, 1H), 8.48 (d, 1H, J= 5.2 Hz), 8.03 (m, 1H), 7.90 (m, 1H), 7.02 (m, 1H), 5.04 (m, 1H), 3.69(m, 1H), 3.49 (m, 2H), 3.36 (m, 1H), 2.62 (m, 1H), 2.52 (m, 1H), 2.26(m, 1H), 1.24 (m, 2H), 1.07 (m, 2H) {5-Cyclopropyl-2-[2-(3,4,6-trifluoro- pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)- pyrrolidin-3-yl-amine 2055

[B4] LCMS: Purity: 99.7399 98%, RT: min, MI: 522 [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-[2-fluoro-4-(2-methyl- 2H-pyrazol-3-yl)-phenyl]- amine 2056

[B4] LCMS: Purity: 98% RT: min, MI: 465.19 (MH)+ 1H-NMR: DMSO 9.78 (s,1H), 9.08 (br s, 2H), 8.97 (br s, 1H), 8.73 (s, 1H), 8.51 (s, 1H), 8.43(d, 1H, J = 5.2 Hz), 8.29 (m, 1H), 7.98 (m, 1H), 7.90 (m, 1H), 5.04 (m,1H), 3.72 (m, 1H), 3.48 (m, 2H), 3.37 (m, 1H), 2.62 (m, 1H), 2.52 (m,1H), 2.26 (m, 1H), 1.24 (m, 2H), 1.06 (m, 2H) {5-Cyclopropyl-2-[2-(3,5,6-trifluoro- pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)- pyrrolidin-3-yl-amine 2057

[B4] LCMS: Purity: 95%, RT: min, MI: 474 (MH)+ 1H-NMR: DMSO 9.02 (s,1H), 8.88 (br s, 2H), 8.84 (s, 1H), 8.20 (m, 2H), 7.83 (s, 1H), 7.70 (d,1H, J = 5.2 Hz), 7.29 (m, 1H), 7.17 (m, 2H), 5.12 (br m, 1H), 3.78 (m,1H), 3.45 (m, 1H), 3.29 (m, 2H), 3.11 (s, 3H), 2.54 (m, 1H), 2.40 (m,1H), 2.25 (m, 1H), 1.26 (m, 2H), 1.01 (m, 2H) {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)- pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl- (R)-pyrrolidin-3-yl-amine 2058

[B4] LCMS: Purity: 100%, RT: min, MI: 465.19 (MH)+ 1H-NMR: DMSO 9.03 (s,1H), 8.90 (s, 1H), 8.69 (br s, 2H), 8.48 (s, 1H), 8.19 (d, 1H, J = 5.2Hz), 7.86 (m, 1H), 7.80 (s, 1H), 7.72 (m, 1H), 7.33 (m, 1H), 7.19 (m,2H), 4.58 (m, 1H), 3.35 (m, 4H), 2.60 (m, 1H), 2.32 (m, 2H), 2.14 (m,1H), 1.94 (m, 3H), 1.22 (m, 2H), 1.11 (m, 1H), 1.05 (m, 1H)Azepan-4-yl-{5- cyclopropyl- 2-[2-(2,6-difluoro- phenylamino)-pyridin-4-yl]-pyrido [3,4-d]pyrimidin-4- yl}-amine 2059

[B4] LCMS: Purity: 101%, RT: min, MI: 465.19 (MH)+ (400 MHz, d6-DMSO,δ): 9.72 (br s, 1H), 9.06 (s, 1H), 8.89 (br s, 2H), 8.23-8.16 (m, 3H),8.08 (s, 1H), 8.02- 7.98 (m, 1H), 7.90 (d, J = 7.3 Hz, 1H), 7.80 (d, J =7.5 Hz, 1H), 7.76 (d, J = 5.5 Hz, 1H), 7.61-7.53 (m, 3H), 3.88 (br s,4H), 3.30 (br s, 4H), 2.71- 2.63 (m, 1H), 1.28-1.23 (m, 2H), 1.11-1.06(m, 2H). [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido [3,4-d]pyrimidin-2-yl)-pyridin-2- yl]-naphthalen-1-yl-amine 2060

[B4] LCMS: Purity: 102%, RT: min, MI: 465.19 (MH)+ (400 MHz, d6-DMSO,δ): 10.69 (br s, 1H), 9.19 (s, 1H), 9.10 (s, 1H), 8.89 (br s, 2H), 8.49(d, J = 5.6 Hz, 1H), 8.46 (s, 1H), 8.32 (br s, 1H), 8.21 (s, 1H), 8.09(d, J = 8.1 Hz, 1H), 7.94- 7.87 (m, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.49(t, J = 7.4 Hz, 1H), 3.97 (br s, 4H), 3.34 (br s, 4H), 2.73- 2.65 (m,1H), 1.30-1.24 (m, 2H), 1.12-1.07 (m, 2H). [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]- iso[D4],[D3]uinolin-3- yl-amine 2061

[B4] LCMS: Purity: 103%, RT: min, MI: 465.19 (MH)+ (400 MHz, d6-DMSO,δ): 10.60 (br s, 1H), 9.11 (s, 1H), 9.05-8.80 (m, 3H), 8.41 (d, J = 5.5Hz, 1H), 8.21 (s, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 5.4 Hz,1H), 7.61 (d, J = 8.6 Hz, 1H), 7.49-7.44 (m, 1H), 7.13 (t, J = 7.5 Hz,1H), 4.05 (s, 3H), 3.59 (br s, 4H), 3.36 (br s, 4H), 2.75-2.67 (m, 1H),1.30-1.24 (m, 2H), 1.12- 1.07 (m, 2H). [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-(1-methyl-1H-indazol-3- yl)-amine 2062

[B4] LCMS: Purity: 104%, RT: min, MI: 465.19 (MH)+ (d6-DMSO) 10.06 (s,1H), 9.06 (s, 1H), 8.73 (s, 1H), 8.70 (br s, 1H), 8.50 (s, 1H), 8.45 (m,1H), 8.37 (br m, 1H), 8.02 (m, 1H), 7.82 (m, 1H), 6.99 (m, 1H), 4.59 (m,1H), 3.40 (m, 2H), 3.13 (m, 2H), 2.66 (m, 1H), 2.34 (m, 2H), 1.90 (m,2H), 1.19 (m, 2H), 1.07 (m, 2H) {5-Cyclopropyl-2- [2-(3,4,6-trifluoro-pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-piperidin-4-yl-amine 2063

[D4], [D3] Method 5: RT: 2.75 min, MI: 482 [M + H] (500 MHz, d6-DMSO)12.09 (brs, 1H), 9.15 (s, 1H), 8.42 (d, 1H), 8.17 (s, 1H), 8.13 (d, 1H),7.48 (d, 1H), 4.10-3.71 (m, 4H), 3.41-3.31 (m, 4H), 2.77- 2.71 (m, 1H),1.69 (s, 6H), 1.28-1.21 (m, 2H), 1.10- 1.05 (m, 2H). 5-Cyclopropyl-4-piperazin-1-yl-2- [2-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-pyrrolo[2,3-b]pyridin-4- yl]-pyrido[3,4-d] pyrimidine 2064

[D4], [D3] Method 5: RT: 3.05 min, MI: 502 [M + H] (500 Mhz, d6-DMSO)11.88 (brs, 1H), 9.12 (s, 1H), 8.29 (d, 1H), 8.16 (s, 1H), 8.07 (d, 1H),7.44 (dd, 2H), 7.33 (t, 2H), 7.23 (d, 1H), 7.19 (t, 1H), 4.08-3.66 (m,4H), 3.36-3.27 (m, 4H), 2.94-2.86 (m, 2H), 2.75- 2.68 (m, 3H), 2.10-2.00(m, 1H), 1.96-1.86 (m, 1H), 1.28-1.21 (m, 2H), 1.11- 1.03 (m, 2H).5-Cyclopropyl-2-[2-(1- phenyl-cyclobutyl)-1H- pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin- 1-yl-pyrido[3,4- d]pyrimidine 2065

[B4] LCMS: Purity: 105%, RT: min, MI: 465.19 (MH)+ (d6-DMSO) 9.76 (s,1H), 9.05 (s, 1H), 8.76 (br m, 1H), 8.63 (s, 1H), 8.50 (s, 1H), 8.40 (brm, 2H), 8.29 (m, 1H), 7.98 (m, 1H), 7.80 (m, 1H), 4.60 (m, 1H), 3.38 (m,2H), 3.15 (m, 2H), 2.66 (m, 1H), 2.32 (m, 2H), 1.94 (m, 2H), 1.19 (m,2H), 1.08 (m, 2H) {5-Cyclopropyl- 2-[2-(3,5,6-trifluoro-pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-piperidin-4-yl-amine 2066

[B4] LCMS: Purity: >90%, RT: min, MI: 465.19 (MH)+ (dmso-d6) 9.16 (br s,3H), 9.10 (s, 1H), 8.24 (s, 1H), 8.10-8.07 (m, 2H), 7.72 (dd, J = 6.7;1.3 Hz, 1H), 4.10- 3.85 (m, 5H), 3.85-3.75 (m, 1H), 3.70-3.60 (m, 1H),3.55-3.20 (m, 2H), 3.34 (br s, 4H), 2.67 (m, 1H), 2.10- 1.95 (m, 1H),1.95-1.75 (m, 4H), 1.55-1.45 (m, 1H), 1.30-1.25 (m, 2H), 1.20- 1.05 (m,2H) [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido [3,4-d]pyrimidin-2-yl)-pyridin-2- yl]-[1-(tetrahydro-furan- 2-yl)-ethyl]-amine 2067

[B4] LCMS: Purity: 107%, RT: min, MI: 465.19 (MH)+ (dmso-d6) 9.18 (br s,2H), 9.06 (s, 1H), 8.21 (s, 1H), 8.10 (d, J = 6.4 Hz, 1H), 7.98 (br s,1H), 7.68 (d, J = 5.4 Hz, 1H), 7.51-7.46 (m, 1H), 7.38-7.30 (m, 1H),7.30-7.17 (m ,2H), 5.33 (br s, 2H), 3.91 (br s, 4H), 3.33 (br s, 4H),2.70-2.62 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.30-1.20 (m, 2H),1.10-1.05 (m, 2H) [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]- [(R)-1-(2-fluoro-phenyl)- ethyl]-amine2068

[D4], [D3] LCMS: Purity: >95%, RT: min, MI: 454 (M + H), (d6-DMSO) 13.13(s, 1H), 9.18 (s, 1H), 8.70 (br m, 1H), 8.63 (d, 1H, J = 4.9 Hz), 8.51(s, 1H), 8.37 (br m, 1H), 8.30 (m, 1H), 7.96 (s, 1H), 7.83 (m, 1H), 4.62(m, 1H), 3.43 (m, 2H), 3.20 (m, 2H), 2.67 (m, 1H), 2.35 (m, 2H), 1.94(m, 2H), 1.20 (m, 2H), 1.08 (m, 2H) [5-Cyclopropyl-2-(2-trifluoromethyl-1H- pyrrolo[2,3-b]pyridin- 4-yl)-pyrido[3,4-d]pyrimidin-4-yl]- piperidin-4-yl-amine 2069

[D4], [D3] LCMS: Purity: >95%, RT: min, MI: 440 (M + H) 1H-NMR: DMSO13.15 (s, 1H), 9.22 (s, 1H), 8.99 (br m, 2H), 8.64 (d, 1H, J = 4.9 Hz),8.52 (s, 1H), 8.28 (m, 1H), 7.99 (s, 1H), 7.89 (m, 1H), 5.08 (m, 1H),3.73 (m, 1H), 3.45 (m, 4H), 2.63 (m, 1H), 2.26 (m, 1H), 1.23 (m, 2H),1.10 (m, 2H) [5-Cyclopropyl-2-(2- trifluoromethyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-pyrido [3,4-d]pyrimidin-4-yl]- (R)-pyrrolidin-3-yl-amine2070

[D4], [D3] LCMS: Purity: >95%, RT: min, MI: 468 (M + H) 1H-NMR: DMSO13.14 (s, 1H), 9.11 (s, 1H), 8.69 (br m, 1H), 8.63 (d, 1H, J = 4.9 Hz),8.32 (br m, 1H), 8.28 (m, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 4.88 (m, 1H),3.46 (m, 2H), 3.12 (m, 5H), 2.07- 2.32 (br m, 5H), 1.23 (m, 2H), 0.98(m, 2H) [5-Cyclopropyl-2-(2- trifluoromethyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-pyrido [3,4-d]pyrimidin-4-yl]- methyl-piperidin-4-yl-amine 2071

[D4], [D3] LCMS: Purity: 99%, RT: min, MI: 474 (M + H 1H-NMR (DMSO-d6,400 MHz): 13.21 (s, 1H), 8.94 (br s, 1H), 8.82 (br s, 1H), 8.67 (d, 1H,J = 4.9 Hz), 8.32 (d, 1H, J = 4.9 Hz), 8.20 (s, 1H), 7.99 (s, 1H), 3.99(br s, 4H), 3.33 (br s, 4H), 2.64 (m, 1H), 1.26 (m, 2H), 1.07 (m, 2H)8-Chloro-5-cyclopropyl- 4-piperazin-1-yl-2-(2- trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4- yl)-pyrido[3,4-d] pyrimidine 2072

[B4] LCMS: Purity: >90%, RT: min, MI: 464 (M + H)+ 1H NMR (400 MHz,DMSO-d6) δ ppm 10.48 (br. s, 1 H) 9.11 (s, 1 H) 8.94 (br. s, 2 H) 8.54(dd, J = 6.8, 0.8 Hz, 1 H) 8.46 (s, 1 H) 8.41 (d, J = 5.5 Hz, 1 H) 8.20(s, 1 H) 7.84 (d, J = 5.5 Hz, 1 H) 7.58 (d, J = 8.8 Hz, 1 H) 7.12-7.30(m, 1 H) 6.68- 6.85 (m, 2 H) 3.95 (br. s., 4 H) 3.35 (br. s., 4 H) 2.60-2.79 (m, 1 H) 1.21-1.32 (m, 2 H) 0.98-1.16 (m, 2 H) [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)- pyridin-2-yl]-pyrazolo[1,5-a]pyridin-2- yl-amine 2073

[B4] Method 5: RT: 1.7 min, MI: 541 [M + H] (DMSO, 400 MHz, 90° C.) 8.96(1H, s), 8.12 (2H, m), 7.51 (1H, s), 7.43 (1H, dd), 4.26 (2H, m), 3.76(1H, m), 3.16 (3H, m), 2.92 (2H, m), 2.71 (1H, m), 2.46 (1H, m), 1.90(2H, m), 1.49 (3H, m), 1.08 (9H, m). {4-[5-Cyclopropyl-4-((cis)-3,5-dimethyl- piperazin-1-yl)-pyrido [3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-[1-(2,2,2- trifluoro-ethyl)-piperidin- 4-yl]-amine 2074

[D4], [D3], [D5] Method 5: RT: 3.29 min, MI: 406 [M + H] (400 MHz,d6-DMSO, 90° C.) 9.06 (1H, s), 8.37 (1H, d, J = 4.9 Hz), 8.13-8.11 (2H,m), 7.42 (1H, s), 3.74- 3.71 (4H, m), 2.94-2.91 (4H, m), 2.72-2.66 (1H,m), 1.28-1.24 (2H, m), 1.01-0.97 (2H, m). 2-(2-Chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-5- cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidine 2075

[D4], [D3] LCMS: Purity: 93%, RT: min, MI: 416.22 (M + H) (dmso-d6)12.00 (br s, 1H), 9.17 (s, 1H), 8.92 (br s, 2H), 8.40 (d, J = 5.1 Hz,1H), 8.20 (s, 1H), 8.15 (d, J = 5.1 Hz, 1H), 7.44 (br s, 1H), 4.66 (s,2H), 3.92 (br s, 4H), 3.39 (br s, 7H), 2.80-2.70 (m, 1H), 1.30-1.25 (m,2H), 1.12-1.10 (m, 2H) 5-Cyclopropyl-2-(2- methoxymethyl-1H-pyrrolo[2,3-b]pyridin- 4-yl)-4-piperazin- 1-yl-pyrido[3,4- d]pyrimidine2076

[B4] LCMS: Purity: >95%, RT: min, MI: 488 (M + H) 1H-NMR: DMSO 13.13 (s,1H), 9.18 (s, 1H), 8.70 (br m, 1H), 8.63 (d, 1H, J = 4.9 Hz), 8.51 (s,1H), 8.37 (br m, 1H), 8.30 (m, 1H), 7.96 (s, 1H), 7.83 (m, 1H), 4.62 (m,1H), 3.43 (m, 2H), 3.20 (m, 2H), 2.67 (m, 1H), 2.35 (m, 2H), 1.94 (m,2H), 1.20 (m, 2H), 1.08 (m, 2H) 4-{5-Cyclopropyl- 2-[2-(2,6-difluoro-phenylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-ylamino}-piperidin-2-one 2077

[D4], [D3] LCMS: Purity: 95%, RT: min, MI: 454 (MH)+ 1H-NMR: DMSO 13.15(s, 1H), 9.22 (s, 1H), 8.99 (br m, 2H), 8.64 (d, 1H, J = 4.9 Hz), 8.52(s, 1H), 8.28 (m, 1H), 7.99 (s, 1H), 7.89 (m, 1H), 5.08 (m, 1H), 3.73(m, 1H), 3.45 (m, 4H), 2.63 (m, 1H), 2.26 (m, 1H), 1.23 (m, 2H), 1.10(m, 2H) [5-Cyclopropyl- 2-(1-methyl-2- trifluoromethyl-1H-pyrrolo[2,3-b]pyridin- 4-yl)-pyrido[3,4-d] pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine 2078

[B4] LCMS: Purity: 94%, RT: min, MI: 475.23 (MH)+ (400 MHz, d6-DMSO, δ):9.13 (s, 1H), 8.95 (br s, 2H), 8.69-8.64 (m, 1H), 8.51- 8.45 (m, 1H),8.23 (s, 1H), 8.21-8.07 (m, 2H), 7.99 (d, J = 8.3 Hz, 1H), 7.85 (t, J =8.0 Hz, 1H), 7.60-7.53 (m, 2H), 3.99 (br s, 4H), 3.36 (br s, 4H),2.75-2.67 (m, 1H), 1.30-1.25 (m, 2H), 1.14- 1.07 (m, 2H).[4-(5-Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]- [D4], [D3]uinolin-2-yl- amine 2079

[D4], [D3] LCMS: Purity: 95%, RT: min, MI: 466.28 (M + H) (dmso-d6)11.76 (s, 1H), 9.19 (s, 1H), 8.93 (br s, 2H), 8.33 (d, J = 5.1 Hz, 1H),8.22 (s, 1H), 8.11 (d, J = 5.1 Hz, 1H), 7.29 (br s, 1H), 5.08 (very brsignal, exch. H's), 3.97 (br s, 4H), 3.40 (br s, 5H), 2.84-2.75 (m, 1H),2.72 (br s, 1H), 2.40 (br s, 1H), 2.11-2.04 (m, 1H), 1.66-1.46 (m, 4H),1.33-1.27 (m, 4H), 1.15- 1.11 (m, 3H) (±)-2-((endo)-2-Bicyclo[2.2.1]hept- 2-yl-1H-pyrrolo [2,3-b]pyridin-4-yl)-5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidine 2080

[D4], [D3] LCMS: Purity: 92%, RT: min, MI: 430.24 (M + H) (dmso-d6)11.92 (br s, 1H), 9.17 (s, 1H), 8.90 (br s, 1H), 8.78 (br s, 1H), 8.72(s, 1H), 8.30 (d, J = 5.0 Hz, 1H), 8.05 (d, J = 5.0 Hz, 1H); 7.34 (br s,1H), 4.57 (s, 2H), 4.25-4.14 (m, 1H), 3.90- 3.60 (m ,4H), 3.40-3.10 (m,4H), 3.28 (s, 3H), 2.50-2.30 (m, 2H), 2.20-2.10 (m ,2H), 2.10-1.90 (m,1H), 1.90- 1.80 (m, 1H) 5-Cyclobutyl-2-(2- methoxymethyl-1H-pyrrolo[2,3-b]pyridin- 4-yl)-4- piperazin-1-yl-pyrido[3,4- d]pyrimidine2081

[D4], [D3] LCMS: Purity: >95%, RT: min, MI: 482 (M + H) 1H-NMR: DMSO13.14 (s, 1H), 9.38 (br m, 1H), 9.12 (s, 1H), 8.63 (d, 1H, J = 4.9 Hz),8.25 (m, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 4.83 (m, 1H), 3.58 (m ,2H),3.26 (m, 2H), 3.12 (s, 3H), 2.84 (d, 3H, J = 4.6 Hz), 2.46 (m, 1H), 2.12(br m, 4H), 1.23 (m, 2H), 1.00 (m, 2H) [5-Cyclopropyl-2-(2-trifluoromethyl-1H- pyrrolo[2,3-b] pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]- methyl-(1-methyl- piperidin-4-yl)-amine 2082

[D4], [D3] Method 5: RT: 3.10 min, MI: 386 [M + H] (500 MHz, d6-DMSO)11.88 (brs, 1H), 9.22 (s, 1H), 8.99 (brs, 1H), 8.86 (brs, 1H), 8.78 (s,1H), 8.38 (s, 1H), 8.12 (s, 1H), 7.65 (d, 1H), 7.46 (d, 1H), 4.32- 4.24(m, 1H), 3.93-3.84 (m, 2H), 3.78-3.69 (m, 2H), 3.41-3.34 (m, 2H), 3.32-3.24 (m, 2H), 2.27-2.18 (m, 2H), 2.15-2.06 (m, 1H), 1.96-1.87 (m, 1H).5-Cyclobutyl-4-piperazin- 1-yl-2-(1H-pyrrolo[2,3- b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine 2083

[B4] LCMS: Purity: >95%, RT: min, MI: 454 (M + H) 1H-NMR: DMSO 9.47 (brm, 1H), 8.98 (s, 1H), 8.87 (s, 1H), 8.18 (d, 2H, J = 4.8 Hz), 7.81 (s,1H), 7.69 (m, 1H), 7.30 (m, 1H), 7.18 (m, 2H), 4.79 (m, 1H), 3.56 (m,2H), 3.24 (m, 2H), 3.09 (s, 3H), 2.84 (d, 3H, J = 4.4 Hz), 2.44 (m, 1H),2.10 (br m, 4H), 1.23 (m, 2H), 0.98 (m, 2H) {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-methyl-(1-methyl- piperidin-4-yl)-amine 2084

[B4] LCMS: Purity: >95%, RT: min, MI: 488 (M + H) 1H-NMR: DMSO 9.45 (brm, 1H), 9.04 (s, 1H), 8.81 (s, 1H), 8.48 (s, 1H), 8.18 (d, 1H, J = 5.3Hz), 7.78 (m, 2H), 7.71 (m, 1H), 7.30 (m, 1H), 7.18 (m, 2H), 4.49 (m,1H), 3.59 (m, 2H), 3.21 (m, 2H), 2.85 (s, 3H), 2.32 (br m, 3H), 1.90 (m,2H), 1.17 (m, 2H), 1.04 (m, 2H) {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-(1-methyl- piperidin-4-yl)-amine 2085

[B4] LCMS: Purity: >95%, RT: min, MI: 516 (M + H) 1H-NMR: DMSO 9.03 (brs, 2H), 8.46 (s, 1H), 8.19 (d, 1H, J = 5.4 Hz), 7.85 (m, 1H), 7.80 (s,1H), 7.73 (m, 1H), 7.32 (m, 1H), 7.21 (m, 2H), 4.52 (m, 1H), 4.35 (m,1H), 3.87 (m, 1H), 3.26 (m, 1H), 2.84 (m, 1H), 2.58 (m, 1H), 2.13 (m,2H), 2.05 (s, 3H), 1.78 (br m, 2H), 1.18 (br m, 2H), 1.04 (m, 2H)1-(4-{5-Cyclopropyl-2- [2-(2,6-difluoro- phenylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-ylamino}-piperidin-1-yl)-ethanone 2086

[D4], [D3] Method 5: RT: 4.06 min, MI: 490 [M + H] (500 MHz, d6-DMSO)11.72 (s, 1H), 9.10 (s, 1H), 8.30 (d, 1H), 8.16 (s, 1H), 8.09 (d, 1H),7.34-7.28 (m, 4H), 7.25-7.19 (m, 2H), 4.12-3.67 (m, 4H), 3.38- 3.28 (m,4H), 2.78-2.70 (m, 1H), 1.81 (s, 6H), 1.28-1.20 (m, 2H), 1.10-1.05 (m,2H). 5-Cyclopropyl-2-[2-(1- methyl-1-phenyl- ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]- 4-piperazin-1-yl-pyrido [3,4-d]pyrimidine 2087

[D3], [D7] 2-(3-Chloro-1H-pyrrolo [2,3-b]pyridin-4-yl)-5-cyclopropyl-4-piperazin- 1-yl-pyrido [3,4-d]pyrimidine 2088

[D4], [D3] LCMS: Purity: >95%, RT: min, MI: 454 (M + H) 1H-NMR: DMSO13.17 (s, 1H), 9.18 (s, 1H), 8.92 (br m, 2H), 8.64 (d, 1H, J = 4.9 Hz),8.23 (m, 2H), 8.00 (s, 1H), 5.20 (m, 1H), 3.78 (m, 1H), 3.27-3.45 (br m,3H), 3.14 (s, 3H), 2.42 (m, 1H), 2.26 (br m, 2H), 1.26 (m, 2H), 1.02 (m,2H) [5-Cyclopropyl-2-(2- trifluoromethyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d] pyrimidin-4-yl]-methyl- (R)-pyrrolidin-3-yl- amine2089

[B4] LCMS: Purity: 96%, RT: min, MI: 475.21 (MH)+ (400 MHz, d6-DMSO, δ):9.13 (s, 1H), 9.05-8.85 (m, 4H), 8.71 (d, J = 4.9 Hz, 1H), 8.35-8.29 (m,1H), 8.24 (s, 1H), 8.22-8.05 (m, 3H), 8.01-7.94 (m, 1H), 7.74- 7.68 (m,1H), 3.95 (br s, 4H), 3.36 (br s, 4H), 2.72- 2.65 (m, 1H), 1.31-1.25 (m,2H), 1.12-1.08 (m, 2H). [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2- yl]-iso[D4], [D3]uinolin- 1-yl-amine2090

[D3] LCMS: Purity: >95%, RT: min, MI: 436 (M + H) 1H-NMR (DMSO-d6, 400MHz): 12.09 (s, 1H), 9.26 (s, 1H), 8.8-9.0 (m, 3H), 8.69 (d, 1H, J = 8.2Hz), 8.59 (d, 1H, J = 5.1 Hz), 7.89 (d, 1H, J = 5.1 Hz), 7.55 (d, 1H, J= 7.9 Hz), 7.49 (m, 1H), 7.19 (m, 1H), 4.32 (m, 1H), 3.83 (m, 4H), 3.30(m, 4H), 2.57 (m, 2H), 2.28 (m, 2H), 2.13 (m, 1H), 1.95 (m, 1H).4-(5-Cyclobutyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)-9H-pyrido[2,3-b] indole 2091

[B01] LCMS: Purity: >95%, RT: min, MI: 382 (M + H) 1H-NMR (DMSO-d6, 400MHz): 12.07 (s, 1H), 9.43 (s, 1H), 8.89 (br s, 2H), 8.73 (d, 1H, J = 5.7Hz), 8.58 (d, 1H, J = 5.1 Hz), 8.55 (d, 1H, J = 8.0 Hz), 8.11 (d, 1H, J= 5.2 Hz), 7.81 (d, 1H, J = 5.1 Hz), 7.55 (d, 1H, J = 8.0 Hz), 7.49 (m,1H), 7.17 (m, 1H), 4.14 (m, 4H), 3.38 (m, 4H). 4-(4-Piperazin-1-yl-pyrido[3,4-d]pyrimidin- 2-yl)-9H-pyrido[2,3-b] indole 2092

[D4], [D3] LCMS: Purity: >95%, RT: min, MI: 420 (M + H) 1H-NMR (CD₃CN,400 MHz): 12.80 (s, 1H), 8.38 (d, 1H, J = 5.8) 8.25 (d, 1H, J = 5.8 Hz),7.87 (s, 1H), 7.57 (s, 1H), 3.99 (m, 4H), 3.24 (m, 4H), 2.55 (m, 4H),1.20 (m, 2H), 0.94 (m, 2H). 8-Chloro-5-cyclopropyl- 2-(2-methyl-1H-pyrrolo[2,3- b]pyridin-4-yl)-4- piperazin-1-yl-pyrido[3,4-d]pyrimidine 2093

[B4] LCMS: Purity: >95%, RT: min, MI: 444 (M + H) 1H-NMR (DMSO-d6, 400MHz): 9.07 (s, 1H), 9.00 (br s, 2H), 8.22 (s, 1H), 8.10 (d, 1H, J = 6.4Hz), 8.02 (br s, 1H), 7.68 (d, 1H, J = 6.4 Hz), 4.67 (m, 1H), 4.48 (m,1H), 3.8-4.0 (m, 5H), 3.32 (m, 4H), 2.66 (m, 1H), 2.10 (m, 1H), 1.5-1.7(m, 4H), 1.47 (m, 1H), 1.25 (m, 2H), 1.08 (m, 2H); (±)-exo-[4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido [3,4-d]pyrimidin-2-yl)-pyridin-2-yl]--7-oxa- bicyclo[2.2.1]hept-2-yl- amine 2094

[B4] LCMS: Purity: >95%, RT: min, MI: 446 (M + H) 1H-NMR: DMSO 9.22 (s,1H), 8.86 (br m, 3H), 8.81 (s, 1H), 8.20 (d, 1H, J = 5.2 Hz), 7.84 (s,1H), 7.71 (m, 1H), 7.38 (m, 1H), 7.27 (m, 1H), 7.17 (m, 2H), 6.11 (br d,1H, J = 17.8 Hz) 5.64 (d, 1H, 11.8 Hz), 3.74 (br s, 4H), 3.32 (br s, 4H)(2,6-Difluoro-phenyl)-[4- (4-piperazin-1-yl-5-vinyl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]-amine 2095

[B4] LCMS: Purity: >95%, RT: min, MI: 446 (M + H) 1H-NMR: DMSO 10.35 (brs, 1H), 9.01 (s, 1H), 8.82 (br m, 1H), 8.64 (s, 1H) 8.41 (m, 2H), 8.30(m, 1H), 8.20 (s, 1H), 8.08 (m, 1H), 8.02 (m, 1H), 4.85 (m, 1H), 3.44(m, 2H), 3.15 (m, 2H), 3.12 (s, 3H), 2.44 (m, 1H), 2.07 (br m, 4H), 1.24(m, 2H), 0.98 (m, 2H) {5-Cyclopropyl-2-[2- (3,5-difluoro-pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine 2096

[B4] LCMS: Purity: >95%, RT: min, MI: 489 (M + H) 1H-NMR: DMSO 8.99 (s,1H), 8.96 (s, 1H), 8.19 (m, 2H), 7.75 (s, 1H), 7.69 (m, 1H), 7.31 (m,1H), 7.20 (m, 2H), 4.77 (m, 1H), 4.56 (m, 1H), 3.94 (m, 1H), 3.16 (m,1H), 3.11 (s, 3H), 2.67 (m, 1H), 2.40 (m, 1H), 2.04 (s, 3H), 1.88 (br m,4H), 1.23 (m, 2H), 0.97 (m ,2H) 1-[4-({5-Cyclopropyl-2-[2-(2,6-difluoro- phenylamino)- pyridin-4-yl]-pyrido[3,4-d]primidin-4-yl}-methyl- amino)-piperidin-1-yl]- ethanone 2097

[B4] LCMS: Purity: >95%, RT: min, MI: 530 (M + H) (400 MHz, d6-DMSO, δ):9.06 (s, 1H), 8.94 (br s, 2H), 8.21 (s, 1H), 8.13 (d, J = 6.3 Hz, 1H),8.00-7.90 (m, 1H), 7.67 (d, J = 6.1 Hz, 1H), 7.33-7.28 (m, 2H), 7.23-7.18 (m, 2H), 4.67-4.60 (m, 1H), 3.90 (br s, 4H), 3.42 (dd, J = 16.1,7.2 Hz, 2H), 3.31 (br s, 4H), 2.96 (dd, J = 16.2, 4.7 Hz, 2H), 2.69-2.62 (m, 1H), 1.28-1.22 (m, 2H), 1.11-1.05 (m, 2H).1-[4-({5-Cyclopropyl- 2-[2-(2,6- difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-methyl-amino)-piperidin-1-yl]- ethanone 2098

[B4] LCMS: Purity: 98%, RT: min, MI: 464.30 (MH)+ (400 MHz, d6-DMSO, δ):9.07 (s, 1H), 8.90 (br s, 2H), 8.21 (s, 1H), 8.15 (d, J = 6.2 Hz, 1H),8.00-7.90 (m, 1H), 7.70-7.64 (m, 1H), 7.39- 7.21 (m, 4H), 5.53-5.45 (m,1H), 3.86 (br s, 4H), 3.31 (br s, 4H), 3.09-3.00 (m, 1H), 2.95-2.86 (m,1H), 2.70-2.56 (m, 2H), 1.99- 1.90 (m, 1H), 1.29-1.23 (m, 2H), 1.11-1.06(m, 2H). [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-yl]-(R)-indan-1-yl- amine 2099

[B4] LCMS: Purity: 98%, RT: min, MI: 464.29 (MH)+ (400 MHz, d6-DMSO, δ):9.07 (s, 1H), 8.96 (br s, 2H), 8.21 (s, 1H), 8.15 (d, J = 6.3 Hz, 1H),8.03-7.95 (m, 1H), 7.71-7.66 (m, 1H), 7.40- 7.22 (m, 4H), 5.52-5.44 (m,1H), 3.91 (br s, 4H), 3.31 (br s, 4H), 3.09-3.01 (m, 1H), 2.96-2.86 (m,1H), 2.70-2.57 (m, 2H), 2.01- 1.90 (m, 1H), 1.29-1.23 (m, 2H), 1.11-1.06(m, 2H). [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-yl]-(S)-indazn-1-yl- amine 2100

[B4] LCMS: Purity: 98%, RT: min, MI: 464.27 (MH)+ 1H-NMR (DMSO-d6, 400MHz): 9.00 (br s, 1H), 8.91 (s, 1H), 8.89 (br s, 1H), 8.21 (d, 1H, J =), 7.95 (s, 1H), 7.85 (s, 1H), 7.71 (dd, 1H, J = ), 7.29 (m, 1H), 7.14-7.21 (m, 2H), 3.94 (br s, 4H), 3.30 (br s, 4H), 2.61 (m, 1H), 1.24 (m,2H), 1.05 (m, 2H) [4-(8-Chloro-5- cyclopropyl-4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro- phenyl)-amine 2101

[B4] LCMS: Purity: >95%, RT: min, MI: 494 (M + H)+ 1H-NMR (DMSO-d6, 400MHz): 8.83 (s, 1H), 8.80 (br s, 2H), 8.20 (d, 1H, J = 5.7 Hz), 7.83 (s,1H), 7.74 (s, 1H), 7.67 (dd, 1H, J = 1.4, 5.3 Hz), 7.27 (m, 1H), 7.11-7.19 (m, 2H), 3.91 (m, 4H), 3.30 (m, 4H), 2.58 (m, 1H), 1.20 (m, 2H),1.00 (m, 2H) [4-(5-Cyclopropyl- 8-fluoro-4-piperazin- 1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2- yl]-(2,6-difluoro-phenyl)- amine 2102

[D4], [D3] LCMS: Purity: >95%, RT: min, MI: 458 (M + H) 1H-NMR (DMSO-d6,400 MHz): 13.22 (s, 1H), 8.86 (br s, 2H), 8.66 (d, 1H, J = 5.0 Hz), 8.28(d, 1H, J = 5.0 Hz), 7.94 (s, 1H), 7.78 (s, 1H), 3.96 (br s, 4H), 3.34(br s, 4H), 2.61 (m, 1H), 1.21 (m, 2H), 1.03 (m, 2H)5-Cyclopropyl-8-fluoro- 4-piperazin-1-yl-2-(2- trifluoromethyl-1H-pyrrolo[2,3-b]pyridin- 4-yl)- pyrido[3,4-d]pyrimidine 2103

[B4] LCMS: Purity: >95%, RT: min, MI: 542 (M + H) 1H-NMR: DMSO 9.23 (brm, 1H), 9.02 (s, 1H), 8.87 (s, 1H), 8.46 (s, 1H), 8.18 (d, 1H, J = 5.3Hz), 8.12 (m, 1H), 7.84 (m, 1H), 7.71 (m, 1H), 7.30 (m, 1H), 7.18 (m,2H), 3.73 (m, 2H), 3.58 (m, 1H), 3.36 (m, 2H), 2.74 (m, 2H), 2.17 (m,5H), 1.98 (m, 2H), 1.73 (m, 3H), 1.48 (m, 2H), 1.25 (m, 2H), 1.00 (m,2H) (1-Cyclobutyl-piperidin- 4-ylmethyl)- {5-cyclopropyl-2-[2-(2,6-difluoro- phenylamino)-pyridin- 4-yl]-pyrido [3,4-d]pyrimidin-4-yl}-amine 2104

[B4] LCMS: Purity: 98%, RT: min, MI: 466.19 (MH)+ (400 MHz, d6-DMSO, δ):10.18 (s, 1H), 9.08 (s, 1H), 8.87 (br s, 2H), 8.54-8.46 (m, 3H), 8.19(s, 1H), 7.92 (dd, J = 5.2, 1.3 Hz, 1H), 7.59 (dd, J = 8.9, 7.5 Hz, 1H),7.47 (d, J = 8.8 Hz, 1H), 3.94 (br s, 4H), 3.34 (br s, 4H), 2.73- 2.65(m, 1H), 1.29-1.24 (m, 2H), 1.12-1.07 (m, 2H). Benzo[1,2,5]oxadiazol-4-yl-[4-(5-cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-yl]-amine 2105

[D4], [D3] Method 5: RT: 4.08 min, MI: 468.53 [M + H] (500 MHz, DMSO)13.18 (1H, s), 9.27 (1H, s), 8.99 (1H, s, br), 8.88 (1H, s, br), 8.74(1H, s), 8.63 (1H, d), 8.25 (1H, d), 7.96 (1H, s), 4.31 (4H, s, br),3.96-3.93 (2H, m, br), 3.89-3.84 (1H, m), 3.77-3.74 (2H, m), 3.61-3.56(1H, m), 2.13-2.12 (2H, m), 1.89-1.67 (6H, m). 5-Cyclopentyl-4-piperazin-1-yl-2- (2-trifluoromethyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d] pyrimidine 2106

[D4], [D3], [D8] Method 5: RT: 3.19 min, MI: 422 [M + H] (400 MHz,d6-DMSO 90° C.) 12.58 (1H, s), 9.06 (1H, s), 8.53 (1H, d, J = 4.9 Hz),8.18 (1H, d, J = 4.9 Hz), 8.11 (1H, s), 7.78 (1H, br m), 7.33 (1H, t, J= 54.2 Hz), 3.93-3.47 (4H, br m), 2.89 (4H, br s), 2.70-2.65 (1H, m),1.29-1.25 (2H, m), 1.06-1.03 (2H, m). 5-Cyclopropyl-2-(2-difluoromethyl-1H- pyrrolo[2,3-b] pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4- d]pyrimidine 2107

[B4] LCMS: Purity: >95%, RT: min, MI: 488 (M + H) 1H-NMR: DMSO 9.02 (s,1H), 8.91 (s, 1H), 8.55 (m, 1H), 8.46 (s, 1H), 8.26 (m, 1H), 8.18 (d,1H, J = 5.3 Hz), 8.09 (m, 1H), 7.81 (s, 1H), 7.71 (m, 1H), 7.31 (m, 1H),7.19 (m, 2H), 3.72 (m, 2H), 3.32 (m, 2H), 2.88 (m, 2H), 2.54 (m, 1H),2.14 (m, 1H), 1.90 (m, 2H), 1.47 (m, 2H), 1.25 (m, 2H), 1.01 (m, 2H){5-Cyclopropyl-2-[2-(2,6- difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}- piperidin-4-ylmethyl- amine2108

[D4], [D3] LCMS: Purity: 93%, RT: min, MI: 458.27 (M + H) (dmso-d6)11.74 (s, 1H), 9.14 (s, 1H), 8.93 (br s, 2H), 8.32 (d, J = 5.2 Hz, 1H),8.18 (s, 1H), 8.09 (d, J = 5.2 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 3.93(br s, 4H), 3.55 (s, 2H), 3.37 (br s, 4H), 3.26 (s, 3H), 2.80-2.71 (m,1H), 1.40 (s, 6H), 1.30-1.20 (m, 2H), 1.12-1.05 (m, 2H)5-Cyclopropyl-2-[2-(2- methoxy-1,1- dimethyl-ethyl)-1H-pyrrolo[2,3-b]pyridin-4- yl]-4-piperazin-1-yl- pyrido[3,4-d]pyrimidine2109

[D4], [D3] LCMS: Purity: 97%, RT: min, MI: 472.29 (M + H) (dmso-d6)11.74 (br s, 1H), 9.21 (s, 1H), 8.99 (br s, 1H), 8.85 (br s, 1H), 8.79(s, 1H), 8.31 (d, J = 5.2 Hz, 1H), 8.07 (d, J = 5.2 Hz, 1H), 7.19 (d, J= 2.2 Hz, 1H), 4.29 (quint, 1H), 3.90-3.70 (m, 4H), 3.54 (s, 2H), 3.40-3.25 (m, 4H), 3.26 (s, 3H), 2.47 (m, 2H), 2.30-2.15 (m, 2H), 2.15-2.05(m, 1H), 1.95-1.85 (m, 1H), 1.40 (s, 6H) 5-Cyclobutyl-2-[2-(2-methoxy-1,1- dimethyl-ethyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl- pyrido[3,4-d[pyrimidine 2110

[B4] LCMS: Purity: >95%, RT: min, MI: 461 (M + H)+ 1H-NMR: DMSO 9.60 (brm, 1H), 8.98 (s, 1H), 8.90 (s, 1H), 8.18 (m, 2H), 7.81 (s, 1H), 7.69 (m,1H), 7.28 (m, 1H), 7.19 (m, 2H), 4.84 (m, 1H), 3.64 (m, 1H), 3.48 (m,2H), 3.09 (s, 3H), 3.05 (m, 2H), 2.45 (m, 1H), 2.07- 2.25 (br m, 8H),1.77 (m, 2H), 1.24 (m, 2H), 0.99 (m, 2H) (1-Cyclobutyl-piperidin-4-yl)-{5-cyclopropyl- 2-[2-(2,6- difluroo-phenylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}- methyl-amine 2111

[D4], [D3] Method 5: RT: 3.20 min, MI: 456 [M + H] (500 MHz, d6-DMSO)11.87 (brs, 1H), 9.16 (s, 1H), 8.31 (d, 1H), 8.16 (s, 1H), 8.08 (d, 1H),7.21 (s, 1H), 4.11-3.73 (m ,4H), 4.00 (dd, 2H), 3.49 (t, 2H), 3.41-3.32(m, 4H), 3.12- 3.04 (m, 1H), 2.78-2.70 (m, 1H), 2.02-1.97 (m, 2H),1.87-1.76 (m, 2H), 1.29- 1.23 (m, 2H), 1.10-1.05 (m, 2H). 5-Cyclopropyl-4-piperazin-1-yl-2- [2-(tetrahydro-pyran-4- yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4- d]pyrimidine 2112

[D4], [D3] Method 5: RT: 3.25 min, MI: 400 [M + H] (500 MHz, d6-DMSO)11.99 (1H, s), 9.25 (1H, s), 9.11 (1H, brs), 8.96 (1H, brs), 8.79 (1H,s), 8.31 (1H, d), 8.13-8.12 (1H, m), 7.22 (1H, s), 4.31-4.24 (1H, m),3.93-3.85 (2H, m), 3.83- 3.72 (2H, m), 3.43-3.34 (2H, m), 3.32-3.21 (2H,m), 2.51 (3H, s), 2.47-2.42 (1H, m), 2.26-2.17 (2H, m), 2.15- 2.06 (1H,m), 1.94-1.87 (1H, m). 5-Cyclobutyl-2-(2- methyl-1H-pyrrolo[2,3-b]pyridin- 4-yl)-4-piperazin-1-yl- pyrido[3,4-d[pyrimidine2113

[D4], [D3] Method 5: RT: 3.18 min, MI: 502 [M + H] (400 MHz, d6-DMSO,90° C.) 11.25 (1H, s), 9.02 (1H, s), 8.63 (1H, s), 8.26 (1H, d, J = 5.0Hz), 8.03 (1H, d, J = 5.0 Hz), 7.45-7.42 (2H, m), 7.37-7.34 (2H, m),7.29- 7.25 (1H, m), 7.01 (1H, s), 4.34-4.30 (1H, m), 3.48 (4H, br s),2.88-2.85 (4H, br. m), 2.55-2.50 (2H, m largely obscured by DMSO peak -visible but broad at lower T), 2.20-2.05 (3H, 5-Cyclobutyl-2-[2-(1-phenyl- cyclopropyl)-1H- pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl- pyrido[3,4-d]pyrimidine m), 1.97-1.92 (1H, m),1.59-1.56 (2H, m), 1.39- 1.36 (2H, m). 2114

[D4], [D3], [D8] Method 5: RT: 2.55 min, MI: 436 [M + H] (400 MHz,d6-DMSO, 90° C.) 9.13 (1H, s), 8.68 (1H, s), 8.51 (1H, d, J = 5.0 Hz),8.16 (1H, d, J = 5.0 Hz), 7.75 (1H, s), 7.23 (1H, t, J = 54.7 Hz),4.36-4.32 (1H, m), 3.64-3.61 (4H, br m), 2.95-2.93 (4H, br. m), 2.56-2.49 (2H, m overlapping with DMSO signal), 2.22- 2.07 (3H, m), 1.99-1.94(1H, m). 5-Cyclobutyl-2-(2- difluoromethyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-4- piperazin-1-yl-pyrido [3,4-d]pyrimidine 2115

[B4] LCMS: Purity: >95%, RT: min, MI: 542 (M + H) 1H-NMR: DMSO 9.20 (brm, 1H), 8.98 (s, 1H), 8.92 (s, 1H), 8.19 (d, 2H, J = 4.5 Hz), 7.83 (s,1H), 7.73 (m, 1H), 7.32 (m, 1H), 7.18 (m, 2H), 4.87 (m, 1H), 3.54 (m,3H), 3.25 (m, 2H), 3.10 (s, 3H), 2.45 (m, 1H), 2.15 (br m, 4H), 1.31 (d,6H, J = 6.6 Hz), 1.26 (m, 2H), 0.99 (m, 2H) {5-Cyclopropyl- 2-[2-(2,6-difluoro-phenylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-(1-isopropyl-piperidin-4-yl)- methyl-amine 2116

[B4] LCMS: Purity: >95%, RT: min, MI: 530 (M + H) (400 MHz, d6-DMSO, δ):10.19 (s, 1H), 9.08 (s, 1H), 8.85 (br s, 2H), 8.76 (s, 1H), 8.57 (d, J =5.3 Hz, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.99 (d, J = 9.6 Hz, 1H), 7.94(dd, J = 5.4, 1.2 Hz, 1H), 7.56 (dd, J = 9.6, 1.8 Hz, 1H), 3.93 (br s,4H), 3.34 (br s, 4H), 2.72-2.65 (m, 1H), 1.29-1.23 (m, 2H), 1.12-1.06(m, 2H). Benzo[1,2,5]oxadiazol-5- yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin- 2-yl]-amine 2117

[B1] LCMS: Purity: >95%, RT: min, MI: 478 (M + H)+ 1H-NMR (DMSO-d6, 400MHz): 13.23 (s, 1H), 9.44 (s, 1H), 8.97 (br s, 1H), 8.85 (s, 1H), 8.77(br s, 1H), 8.66 (d, 1H, J = 5.0 Hz), 8.28 (d, 1H, J = 5.0 Hz), 7.97 (s,1H), 3.7-4.0 (m, 8H) 5-Bromo-4-piperazin- 1-yl- 2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4- yl)-pyrido[3,4-d] pyrimidine 2118

[D4], [D3] LCMS: Purity: >95%, RT: min, MI: 462 (M + H) 1H-NMR (DMSO-d6,400 MHz): 11.80 (s, 1H), 8.96 (br s, 1H), 8.77 (br s, 1H), 8.32 (d, 1H,J = 5.1 Hz), 8.11 (d, 1H, J = 5.1 Hz), 7.95 (s, 1H), 7.49 (d, 1H, J =2.3 Hz), 3.9-4.0 (m, 4H), 3.33 (m, 4H), 2.67 (m, 2H), 1.43 (s, 9H), 1.25(m, 2H), 1.06 (m, 2H) 2-(2-tert-Butyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-8-chloro- 5-cyclopropyl-4- piperazin-1-yl-pyrido [3,4-d]pyrimidine2119

[D4], [D3] LCMS: Purity: >95%, RT: min, MI: 446 (M + H) 1H-NMR (DMSO-d6,400 MHz): 11.80 (s, 1H), 8.88 (br s, 2H), 8.32 (d, 1H, J = 5.1 Hz), 8.08(d, 1H, J = 5.1 Hz), 7.73 (s, 1H), 7.21 (d, 1H, J = 2.3 Hz), 3.9-4.0 (m,4H), 3.34 (m ,4H), 2.67 (m, 1H), 1.43 (s, 9H), 1.21 (m, 2H), 1.01 (m,2H) 2-(2-tert-Butyl-1H- pyrrolo[2,3-b]pyridin- 4-yl)-5-cyclopropyl-8-fluoro-4- piperazin-1-yl-pyrido [3,4-d]pyrimidine 2120

[D4], [D3] LCMS: Purity: >95%, RT: min, MI: 466 (M + H) 1H-NMR (DMSO-d6,400 MHz): 11.82 (s, 1H), 9.35 (s, 1H), 9.01 (br s, 1H), 8.81 (s, 1H),8.79 (br s, 1H), 8.32 (d, 1H, J = 5.2 Hz), 8.08 (d, 1H, J = 5.2 Hz),7.16 (d, 1H, J = 2.2 Hz), 3.7-4.0 (m ,4H), 3.37 (m, 4H), 1.44 (s, 9H)5-Bromo-2-(2- tert-butyl-1H-pyrrolo [2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido [3,4-d]pyrimidine 2121

[D4], [D3] LCMS: Purity: 95%, RT: min, MI: 468.26 (dmso-d6) 11.70 (s,1H), 9.15 (s, 1H), 8.94 (br s, 2H), 8.30 (d, J = 5.2 Hz, 1H), 8.17 (s,1H), 8.09 (d, J = 5.2 Hz, 1H), 7.20 (s, 1H), 4.74- 4.70 (m, 1H), 4.63(qpp d, J = 3.7 Hz, 1H), 3.93 (br s, 4H), 3.36 (br s, 4H), 3.24 (dd, J =8.8; 4.8 Hz, 1H), 2.80-2.70 (m, 1H), 2.10 1.95 (m, 2H), 1.67-1.50 (m,4H), 1.30-1.20 (m, 2H), 1.15-1.05 (m, 2H) (±)-exo-5- Cyclopropyl-2-[2-(7-oxa-bicyclo[2.2.1] hept-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl- pyrido[3,4-d]pyrimidine 2122

[D4], [D3] LCMS: Purity: 97%, RT: min, MI: 482.24 (M + H) (dmso-d6)11.70 (br s, 1H), 9.22 (s, 1H), 8.98 (br s, 1H), 8.88 (br s, 1H), 8.78(s, 1H), 8.30 (d, J = 5.2 Hz, 1H), 8.08 (d, J = 5.2 Hz, 1H), 7.18 (s,1H), 4.73-4.70 (m, 1H), 4.63 (d, J = 3.6 Hz, 1H), 4.28 (app quint, 1H),3.95-3.75 (m, 4H), 3.45- 3.30 (m, 4H), 3.23 (dd, J = 8.8; 4.8 Hz, 1H),2.50-2.40 (m, 2H), 2.30-2.15 (m, 2H), 2.15-2.00 (m, 2H), 2.00- 1.85 (m,2H), 1.75-1.55 (m, (±)-dxo-5- Cyclobutyl-2-[2-(7-oxa-bicyclo[2.2.1]hept-2- yl)-1H-pyrrolo[2,3-b] pyridin-4-yl]-4-piperazin-1-yl- pyrido[3,4-d]pyrimidine 4H) 2123

[B4] LCMS: Purity: >95%, RT: min, MI: 552 (MH)+ 1H-NMR: DMSO 8.98 (s,1H), 8.91 (s, 1H), 8.19 (d, 2H, J = 4.2 Hz), 7.81 (s, 1H), 7.68 (m, 1H),7.32 (m, 1H), 7.18 (m, 2H), 6.55 (br m, 1H), 4.80 (m, 1H), 3.63 (br m,4H), 3.31 (m, 2H), 3.10 (s, 3H), 2.44 (m, 1H), 2.08 (br m, 4H), 1.24 (m,2H), 0.99 (m, 2H) {5-Cyclopropyl-2- [2-(2,6- difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}- [1-(2,2-difluoro-ethyl)-piperidin-4- yl]-methyl-amine 2124

[B4] LCMS: Purity: 96%, RT: min, MI: 464.28 (MH)+ (400 MHz, d6-DMSO, δ):9.35 (s, 1H), 9.06 (s, 1H), 8.86 (br s, 2H), 8.26 (d, J = 5.6 Hz, 1H),8.18 (s, 1H), 7.94 (s, 1H), 7.68 (dd, J = 5.4, 1.3 Hz, 1H), 7.66 (s,1H), 7.39 (dd, J = 8.0, 1.7 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 3.92 (brs, 4H), 3.33 (br s, 4H), 2.89-2.79 (m, 4H), 2.73-2.65 (m, 1H), 2.07-1.98 (m, 2H), 1.28-1.23 (m, 2H), 1.11-1.06 (m, 2H). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d] pyrimidin-2-yl)-pyridin-2-yl]-indan-5-yl-amine 2125

[B4] Method 5: RT: 2.88 min, MI: 529 [M + H] (500 MH, d6-DMSO) 9.69 (1H,s), 9.06 (1H, s), 8.82 (1H, s), 8.43 (1H, d), 8.21 (1H, s), 7.98 (1H,dd), 7.56 (1H, m), 3.93 (4H, s), 3.36 (2H, s,), 1.95 (1H, m), 1.39 (3H,m), 1.28 (3H, m), 1.06 (2H, m), 0.98 (2H, m), 0.79 (2H, m).(5-Cyclopropyl- 3,6-difluoro- pyridin-2-yl)-{4-[5- cyclopropyl-4-(3,3-dimethyl-piperazin- 1-yl)-pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2-yl}-amine 2126

[B4] LCMS: Purity: 98%, RT: min, MI: 502.1 (MH)+ (400 MHz, d6-DMSO, δ):11.53 (s, 1H), 9.09 (s, 1H), 9.00 (s, 1H), 8.89 (br s, 2H), 8.61 (dd, J= 5.2, 0.5 Hz, 1H), 8.21-8.18 (m, 2H), 7.79-7.75 (m, 2H), 7.64-7.55 (m,3H), 3.92 (br s, 4H), 3.37- 3.28 (m, 4H), 2.72-2.64 (m, 1H), 1.28-1.22(m, 2H), 1.11-1.05 (m, 2H). N-[4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d] pyrimidin-2-yl)-pyridin- 2-yl]-2,2-difluoro-2-phenyl-acetamide 2127

[D4], [D3] Method 5: RT: 3.40 min, MI: 430 [M + H] (600 MHz, d6-DMSO)12.06 (1H, s), 9.08 (1H, s), 8.37 (1H, d, J = 5.0 Hz), 9.11-8.10 (2H,m), 7.45 (1H, br d, J = 1.6 Hz), 3.96- 3.51 (4H, bery broad m), 2.94(4H, br s), 2.70-2.66 (1H, m), 1.58-1.542H, m), 1.36-1.34 (2H, m), 1.27-1.24 (2H, m), 1.05-1.04 (2H, m). 5-Cyclopropyl-2-[2-(1-fluoro-cyclopropyl)-1H- pyrrolo[2,3-b]pyridin- 4-yl]-4-piperazin-1-yl-pyrido[3,4- d]pyrimidine 2128

[B4] LCMS: Purity: >95%, RT: min, MI: 505 (MH)+ 1H-NMR: DMSO 9.65 (br s,1H), 9.27 (s, 1H), 8.86 (s, 1H), 8.57 (s, 1H), 8.25 (d, 1H, J = 5.3 Hz),7.85 (s, 1H), 7.72 (m, 1H), 7.30 (m, 1H), 7.19 (m, 2H), 4.3 5 (m, 1H),3.61 (m, 2H), 3.30 (m, 2H), 2.88 (s, 3H), 2.46 (m, 1H), 2.27 (m, 2H),1.93 (m, 2H), 1.22 (m, 2H), 1.07 (m, 2H) {4-[5-Cyclopropyl-4-(1-methyl-piperidin-4- yslulfanyl)-pyrido[3,4- d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6- difluoro-phenyl)-amine 2129

[B4] LCMS: Purity: >95%, RT: min, MI: 503 (MH)+ 1H-NMR: DMSO 10.33 (brs, 1H), 9.62 (br s, 1H), 9.01 (s, 1H), 8.61 (s, 1H), 8.41 (d, 1H, J =5.7 Hz), 8.31 (m, 1H), 8.20 (s, 1H), 8.07 (m, 1H), 7.99 (m, 1H), 4.80(m, 1H), 3.57 (m, 2H), 3.20 (m, 2H), 3.12 (s, 3H), 2.82 (m, 3H), 2.44(m, 1H), 2.07 (br m, 4H), 1.25 (m, 2H), 0.99 (m, 2H) {5-Cyclopropyl-2-[2-(3,5-difluoro- pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}- methyl-(1-methyl- piperidin-4-yl)-amine 2130

[B4] LCMS: Purity: 90.012%, RT: min, MI: 522 [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d] pyrimidin-2-yl)-pyridin-2-yl]-[2-fluoro-4-(1- methyl-1H-pyrazol-4-yl)- phenyl]-amine 2131

[B4] LCMS: Purity: 98%, RT: min, MI: 450.0 (MH)+ (400 MHz, d6-DMSO, δ):9.52 (s, 1H), 8.96 (s, 1H), 8.83 (br s, 2H), 8.31 (d, J = 5.5 Hz, 1H),8.18 (s, 1H), 7.95 (s, 1H), 7.75-7.70 (m, 3H), 7.34-7.29 (m, 2H), 6.96(t, J = 8.0 Hz, 1H), 4.12- 4.06 (m, 2H), 3.88-3.82 (m, 2H), 3.45-3.35(m, 2H), 3.15-2.95 (m, 4H), 2.45- 2.37 (m, 1H), 1.31-1.25 (m, 2H),1.04-0.98 (m, 2H). {4-[5-Cyclopropyl-4- (hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- pyrido[3,4-d] pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine 2132

[B4] LCMS: Purity: 97%, RT: min, MI: 487.0 (MH)+ (400 MHz, d6-DMSO, δ):10.27 (s, 1H), 8.99 (s, 1H), 8.86 (br s, 2H), 8.72 (s, 1H), 8.41 (d, J =5.5 Hz, 1H), 8.29 (d, J = 2.6 Hz, 1H), 8.20 (s, 1H), 8.10-8.04 (m, 1H),7.99 (dd, J = 5.7, 1.4 Hz, 1H), 4.14-4.08 (m, 2H), 3.89- 3.83 (m, 2H),3.45-3.35 (m, 2H), 3.15-2.95 (m, 4H), 2.44-2.36 (m, 1H), 1.31- 1.26 (m,2H), 1.04-0.99 (m, 2H). {4-[5-Cyclopropyl-4- (hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- pyrido[3,4-d] pyrimidin-2-yl]-pyridin-2-yl)-(3,5-difluoro- pyridin-2-yl)-amine 2133

[B4] LCMS: Purity: 96%, RT: min, MI: 533.18 (MH)+ (400 MHz, d6-DMSO, δ):9.76 (s, 1H), 9.07 (s, 1H), 8.87 (br s, 2H), 8.67 (d, J = 2.1 Hz, 1H),8.42 (d, J = 5.3 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.88 (d, J = 9.1Hz, 1H), 7.80-7.76 (m, 2H), 3.92 (br s, 4H), 3.34 (br s, 4H), 2.74-2.65(m, 1H), 1.29-1.23 (m, 2H), 1.11- 1.06 (m, 2H). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d] pyrimidin-2-yl)-pyridin-2-yl]-(2-trifluoromethyl- benzooxazol-5-yl)-amine 2134

[D4], [D3] LCMS: Purity: 95%, RT: min, MI: 471 (MH)+ 1H-NMR: DMSO 13.25(s, 1H), 9.46 (s, 1H), 8.70 (m, 2H), 8.59 (s, 1H), 8.49 (m, 1H), 8.32(m, 1H), 8.05 (s, 1H), 4.58 (m, 1H), 3.40 (m, 2H), 3.28 (m, 2H), 2.56(m, 1H), 2.40 (m, 2H), 1.97 (m, 2H), 1.24 (m, 2H), 1.08 (m, 2H)5-Cyclopropyl- 4-(piperidin- 4-ylsulfanyl)-2-(2- trifluoromethyl-1H-pyrrolo[2,3-b] pyridin-4-yl)- pyrido[3,4-d]pyrimidine 2135

[D4], [D3] LCMS: Purity: 97%, RT: min, MI: 480.1 (M + H) 1H-NMR(dmso-d6): 11.76 (s, 1H), 9.24 (s, 1H), 9.03 (br s, 1H), 8.92 (br s,1H), 8.79 (s, 1H), 8.29 (d, J = 5.2 Hz, 1H), 8.07 (d, J = 5.2 Hz, 1H),7.25 (s, 1H), 4.29 (quint, J = 8.8 Hz, 1H), 3.88 (br s, 2H), 3.79 (br s,2H), 3.40-3.20 (m, 5H), 2.69 (br s, 1H), 2.50-2.40 (m, 2H), 2.36 (br s,1H), 2.30-1.80 (m, 5H), 1.70-1.40 (m, 4H), 1.30-1.20 (m, 2H), 1.15- 1.05(m, 1H) (±) endo-2-(2- Bicyclo[2.2.1]hept- 2-yl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5- cyclobutyl-4-piperazin-1- yl-pyrido[3,4-d]pyrimidine 2136

[D4], [D3] LCMS: Purity: 95%, RT: min, MI: 502 (M + H) 1H-NMR: DMSO13.16 (s, 1H), 8.75 (m, 1H), 8.65 (d, 1H, J = 4.9 Hz), 8.37 (m, 1H),8.32 (m, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 4.95 (m, 1H), 3.47 (m, 2H),3.21 (m, 2H), 3.11 (s, 3H), 2.40 (m, 1H), 1.91-2.18 (br m, 4H),1.14-1.33 (br m, 2H), 0.96 (m, 2H) [8-Chloro-5- cyclopropyl-2-(2-trifluoromethyl-1H- pyrrolo[2,3-b]pyridin- 4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-methyl- piperidin-4-yl-amine 2137

[B4] LCMS: Purity: 95%, RT: min, MI: 478.27 (MH)+ (400 MHz, d6-DMSO, δ):9.07 (s, 1H), 8.94 (br s, 2H), 8.22 (s, 1H), 8.10 (d, J = 6.2 Hz, 1H),8.02 (br s, 1H), 7.69-7.64 (m, 1H), 7.17- 7.11 (m, 4H), 4.21-4.13 (m,1H), 3.93 (br s, 4H), 3.32 (br s, 4H), 3.20 (dd, J = 16.5, 5.2 Hz, 1H),2.94 (t, J = 6.3 Hz, 2H), 2.80 (dd, J = 16.4, 8.4 Hz, 1H), 2.70-2.63 (m,1H), 2.20-2.13 (m, 1H), 1.89-1.77 (m, 1H), 1.29- 1.23 (m ,2H), 1.11-1.06(m, [4-(5-Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2- yl]-(1,2,3,4-tetrahydro- naphthalen-2-yl)-amine 2H).2138

[B4] LCMS: Purity: 95%, RT: min, MI: 503 (M + H) 1H-NMR: DMSO 12.20 (brs, 1H), 9.03 (s, 1H), 8.84 (m, 1H), 8.69 (d, 2H, J = 5.7 Hz), 8.57 (m,1H), 8.45 (m, 1H), 8.22 (m, 3H), 8.04 (m, 1H), 7.88 (m, 1H), 7.61 (m,1H), 7.56 (m, 1H), 4.89 (m, 1H), 3.45 (m, 2H), 3.19 (m, 2H), 3.15 (s,3H), 2.45 (m, 1H), 2.07 (br m, 4H), 1.26 (m, 2H), 1.00 (m, 2H){5-Cylcopropyl-2-[2- ([D4], [D3]uinolin-2- ylamino)-pyridin-4-yl]-pyrido[3,4-d] pyrimidin-4- yl}-methyl-piperidin- 4-yl-amine 2139

[D4], [D3] LCMS: Purity: 95%, RT: min, MI: 482 (M + H) 1H-NMR: DMSO13.15 (s, 1H), 9.09 (s, 1H), 8.63 (d, 1H, J = 4.9 Hz), 8.48 (m, 1H),8.25 (d, 1H, J = 4.9 Hz), 8.16 (s, 1H), 8.04 (m, 1H), 7.96 (s, 1H), 3.31(s, 3H), 3.17 (m, 2H), 2.78 (m, 2H), 2.43 (m, 1H), 2.23 (m, 1H),1.50-1.75 (br m, 2H), 1.30 (br m, 2H), 1.03 (br m, 6H)[5-Cyclopropyl-2-(2- trifluoromethyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-pyrido [3,4-d]pyrimidin-4-yl]- methyl-piperidin-4-ylmethyl-amine 2140

[B4] LCMS: Purity: 97%, RT: min, MI: 480.1 (MH)+ (400 MHz, d6-DMSO, δ):9.08 (s, 1H), 8.94 (br s, 2H), 8.29-8.17 (m, 2H), 8.12 (d, J = 5.9 Hz,1H), 7.70 (d, J = 6.9 Hz, 1H), 7.36-7.23 (m, 4H), 5.41-5.35 (m, 1H),4.71-4.66 (m, 1H), 3.92 (br s, 4H), 3.31 (br s, 4H), 3.15 (dd, J = 16.3,5.7 Hz, 1H), 2.93 (dd, J = 16.3, 2.5 Hz, 1H), 2.70-2.62 (m, 1H),1.29-1.23 (m, 2H), 1.11- 1.06 (m, 2H). (1S,2R)-1- [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-ylamino]-indan-2-ol 2141

[B4] LCMS: Purity: 98%: RT: min, MI: 480.1 (MH)+ (400 MHz, d6-DMSO, δ):9.08 (s, 1H), 8.98 (br s, 2H), 8.22 (s, 1H), 8.15 (d, J = 6.4 Hz, 1H),8.09 (br s, 1H), 7.72 (d, J = 6.2 Hz, 1H), 7.32-7.22 (m, 4H), 5.30- 5.24(m, 1H), 4.39 (dd, J = 13.9, 7.1 Hz, 1H), 3.92 (br s, 4H), 3.32 (br s,4H), 3.25 (dd, J = 1.5.7, 7.2 Hz, 1H), 2.83 (dd, J = 15.4, 7.5 Hz, 1H),2.70-2.62 (m, 1H), 1.29-1.23 (m, 2H), 1.11- 1.06 (m, 2H). (1S,2S)-1-[4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido [3,4-d]pyrimidin-2-yl)-pyridin-2- ylamino]-indan-2-ol 2142

[B4] LCMS: Purity: 98%, RT: min, MI: 480.1 (MH)+ (400 MHz, d6-DMSO, δ):9.08 (s, 1H), 8.94 (br s, 2H), 8.29-8.17 (m, 2H), 8.13 (d, J = 6.1 Hz,1H), 7.71 (d, J = 5.6 Hz, 1H), 7.36-7.23 (m, 4H), 5.41-5.35 (m, 1H),4.70-4.65 (m, 1H), 3.92 (br s, 4H), 3.31 (br s, 4H), 3.15 (dd, J = 16.1,5.4 Hz, 1H), 2.93 (dd, J = 16.1, 2.6 Hz, 1H), 2.70-2.62 (m, 1H),1.29-1.23 (m, 2H), 1.11- 1.06 (m, 2H). (1R,2S)-1- [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d]pyrimidin- 2-yl)-pyridin-2-ylamino]-indan-2-ol 2143

[B4] LCMS: Purity: 99%, RT: min, MI: 480.1 (MH)+ (400 MHz, d6-DMSO, δ):9.09 (s, 1H), 9.04 (br s, 2H), 8.23 (s, 1H), 8.16 (d, J = 6.5 Hz, 1H),8.13 (br s, 1H), 7.74 (d, J = 6.2 Hz, 1H), 7.34-7.23 (m, 4H), 5.27 (t, J= 6.8 Hz, 1H), 4.39 (dd, J = 13.9, 7.1 Hz, 1H), 3.91 (br s, 4H), 3.32(br s, 4H), 3.25 (dd, J = 15.6, 7.1 Hz, 1H), 2.83 (dd, J = 15.5, 7.6 Hz,1H), 2.70-2.62 (m, 1H), 1.30-1.23 (m, 2H), 1.11- 1.06 (m, 2H).(1R,2R)-1-[4-(5- Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2- yl)-pyridin-2-ylamino]- indan-2-ol 2144

[D4], [D3] LCMS: Purity: 83%, RT: min, MI: 498.0 (M + H) (dmso-d6) 9.16(br s, 1H), 8.83 (br s, 1H), 8.74 (br s, 2H), 8.41 (d, J = 4.8 Hz, 1H),8.12 (d, J = 4.8 Hz, 1H), 7.70 (br s, 1H), 7.55- 7.46 (m, 1H), 7.30-7.22(m, 2H), 4.30-4.15 (m, 1H), 3.90-3.60 (m, 4H), 3.40- 3.15 (m, 4H),2.45-2.35 (m, 2H), 2.20-2.10 (m, 2H), 2.10-1.98 (m, 1H), 1.90- 1.80 (m,1H) 5-Cyclobutyl-2-[2-(2,6- difluoro-phenyl)-1H- pyrrolo[2,3-b]pyridin-4-yl]-4- piperazin-1-yl-pyrido [3,4-d]pyrimidine 2145

[D4], [D3] LCMS: Purity: 95%, RT: min, MI: 484.2 (M + H) (dmso-d6) 12.23(d, J = 1.3 Hz, 1H), 9.14 (s, 1H), 8.91 (br s, 2H), 8.49 (d, J = 5.0 Hz,1H), 8.19 (d, J = 5.0 Hz, 1H), 8.18 (s, 1H), 7.78 (br s, 1H), 7.56 (m,1H), 7.33 (m, 2H), 3.93 (br s, 4H), 3.36 (br s, 4H), 2.75 (m, 1H),1.30-1.23 (m, 2H), 1.12- 1.06 (m, 2H) 5-Cyclopropyl-2-[2-(2,6-difluoro-phenyl)-1H- pyrrolo[2,3-b]pyridin- 4-yl]-4-piperazin-1-yl-pyrido[3,4- d]pyrimidine 2146

[D4], [D3] LCMS: Purity: 96%, RT: min, MI: 426.1 (M + H) (dmso-d6) 11.82(br s, 1H), 9.16 (s, 1H), 8.93 (br s, 2H), 8.30 (d, J = 5.2 Hz, 1H),8.17 (s, 1H), 8.09 (d, J = 5.2 Hz, 1H), 7.24 (d, J = 1.7 Hz, 1H), 3.91(br s, 4H), 3.74 (quint, J = 8.4 Hz, 1H), 3.37 (br s, 4H), 2.75 (m, 1H),2.45-2.75 (m, 4H), 2.35- 1.98 (m, 1H), 1.96-1.85 (m, 1H), 1.30-1.22 (m,2H), 1.12-1.08 (m, 2H) 2-(2-Cyclobutyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-5- cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidine2147

[D4], [D3] LCMS: Purity: 92%, RT: min, MI: 440.28 (M + H) (dmso-d6)11.89 (br s, 1H), 9.25 (s, 1H), 9.10 (br s, 1H), 8.94 (br s, 1H), 8.79(s, 1H), 8.30 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 5.2 Hz, 1H), 7.23 (d, J= 1.6 Hz, 1H), 4.29 (quint, 1H), 3.88 (br s, 2H), 3.79 (br s, 2H), 3.75(quint, J = 8.8 Hz, 1H), 3.50-3.20 (m, 4H), 2.50- 2.43 (m, 2H),2.43-2.31 (m, 4H), 2.31-2.16 (m, 2H), 2.16-1.97 (m, 2H), 1.97- 1.07 (m,2H) 5-Cyclobutyl-2-(2- cyclobutyl- 1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin- 1-yl-pyrido[3,4-d] pyrimidine 2148

[B4] LCMS: Purity: 98%, RT: min,, MI: 495 (M + H) 1H NMR (400 MHz,DMSO-d6) 9.80-10.03 (1 H, m), 8.83-9.14 (2 H, m), 8.81 (1 H, s), 8.43 (1H, d, J = 5.5 Hz), 8.26 (1 H, d, J = 2.5 Hz), 7.90-8.08 (3 H, m), 3.97(4 H, br. s.), 3.32 (4 H, br. s.), 2.57-2.64 (1 H, m), 1.18-1.30 (2 H,m), 1.01-1.11 (2 H, m) [4-(8-Chloro- 5-cyclopropyl-4-piperazin-1-yl-pyrido [3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]-(3,5-difluoro-pyridin- 2-yl)-amine 2149

[B4] LCMS: Purity: 98%, RT: min, MI: 478.24 (MH)+ (400 MHz, d6-DMSO, δ):9.91 (s, 1H), 9.34 (s, 1H), 9.07 (s, 1H), 8.97 (br s, 2H), 8.68 (d, J =1.4 Hz, 1H), 8.45 (d, J = 5.3 Hz, 1H), 8.20 (s, 1H), 8.04 (s, 1H), 7.82(dd, J = 5.4, 1.4 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 9.0,1.8 Hz, 1H), 4.03 (s, 3H), 3.93 (br s, 4H), 3.35 (br s, 4H), 2.74-2.65(m, 1H), 1.29-1.23 (m, 2H), 1.11-1.06 (m, 2H). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d] pyrimidin-2-yl)-pyridin-2-yl]-(3-methyl-3H- benzimidazol-5-yl)-amine 2150

[B4] Method 5: RT: 2.34 min, MI: 522 [M + H] (500 MH, DMSO) 9.43 (1H,s), 9.06 (1H, s), 8.29 (1H, d), 8.18 (1H, s), 7.91 (1H, s), 7.68 (3H,m), 7.05 (2H, d), 4.72 (2H, m), 3.91 (4H, s, broad), 3.33 (4H, s,), 2.69(1H, m), 1.26 (2H, m), 1.08 (2H, m). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]-[4-(2,2,2-trifluoro- ethoxy)-phenyl]-amine 2151

[B4] LCMS: Purity: >95%, RT: min, MI: 506 (MH)+ 1H-NMR: DMSO 10.29 (brs, 1H), 9.01 (s, 1H), 8.80 (br m, 1H), 8.73 (s, 1H), 8.45 (d, 1H, J =5.5 Hz), 8.38 (br m, 1H), 8.27 (m, 1H), 8.20 (s, 1H), 8.10 (m, 1H), 8.03(m, 1H), 4.84 (m, 1H), 3.44 (m, 2H), 3.15 (m, 2H), 3.12 (s, 3H), 2.44(m, 1H), 2.07 (br m, 4H), 1.25 (m, 2H), 0.98 (m, 2H) {2-[2-(5-Chloro-3-fluoro-pyridin-2- ylamino)-pyridin- 4-yl]-5-cyclopropyl- pyrido[3,4-d]pyrimidin-4-yl}- methyl-piperidin-4-yl- amine 2152

[D4], [D3] LCMS: Purity: 95%, RT: min, MI: 454.23 (M + H) (dmso-d6)11.71 (d, J = 1.3 Hz, 1H), 9.09 (s, 1H), 8.89 (br s, 2H), 8.23 (d, J =5.2 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J = 5.2 Hz, 1H), 7.11 (d, J = 1.7Hz, 1H), 3.84 (br s, 4H), 3.30 (br s, 4H), 2.76 (m, 1H), 2.68 (m, 1H),2.15 (m, 2H), 1.77 (m, 2H), 1.67 (m, 1H), 1.51 (m, 2H), 1.36 (m, 2H),1.28-1.13 (m, 3H), 1.06-0.80 (m, 2H) 5-Cyclopropyl-2-(2- cyclohexyl-1H-pyrrolo[2,3-b]pyridin- 4-yl)-4-piperazin- 1-yl-pyrido[3,4-d] pyrimidine2153

[D4], [D3] LCMS: Purity: 94%, RT: min, MI: 468.28 (dmso-d6) 11.72 (s,1H), 9.17 (s, 1H), 8.99 (br s, 1H), 8.84 (br s, 1H), 8.72 (s, 1H), 8.22(d, J = 5.3 Hz, 1H), 8.01 (d, J = 5.3 Hz, 1H), 7.1 (d, J = 1.8 Hz, 1H),6.28 (br s, esch. protons), 4.11 (m, 1H), 3.76 (m, 4H), 3.17 (m, 4H),2.75 (m, 1H), 2.42 (m, 2H), 2.15 (m, 2H), 2.58- 1.95 (m, 3H), 1.77 (m,4H), 1.50 (m, 2H), 1.35 (m, 2H), 1.24 (m, 1H) 5-Cyclobutyl-2-(2-cyclohexyl- 1H-pyrrolo[2,3-b] pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d] pyrimidine 2154

[B4] LCMS: Purity: 94%, RT: min, MI: 593.17 (M + H) (dmso-d6) 9.10 (s,1H), 9.05 (br s, 1H), 9.02 (br s, 1H), 8.92 (br s, 2H), 8.53 (s, 1H),8.49 (dd, J = 8.3, 2.3 Hz, 1H), 8.36 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H),8.10 (d, J = 8.3 Hz, 1H), 8.06 (s, 1H), 7.77 (dd, J = 5.3, 1.3 Hz, 1H),3.88 (br s, 4H), 3.37 (br s,4H), 2.71 (m, 1H), 1.28 (m, 2H), 1.12 (m,2H) [3-Chloro-1-(5- trifluoromethyl- pyridin-2-yl)-1H-pyrazol-4-yl]-[4-(5- cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-amine 2155

[D4], [D3] LCMS: Purity: >95%, RT: min, MI: 490 (M + H) 1H-NMR: DMSO13.14 (s, 1H), 9.73 (br m, 1H), 9.35 (br m, 1H), 9.26 (s, 1H), 8.64 (d,1H, J = 4.9 Hz), 8.56 (s, 1H), 8.34 (d, 1H, J = 4.9 Hz), 7.97 (m, 2H),5.50 (m, 1H), 4.02 (m, 1H), 3.82-3.90 (br m,1H), 3.45 (m, 2H), 2.61 (m,1H), 2.54 (m, 1H), 2.08 (m, 1H), 1.21 (m, 3H), 1.05 (m, 1H)[5-Cyclopropyl-2-(2- trilfuoromethyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-pyrido [3,4-d]pyrimidin-4-yl]- (3,3-difluoro-piperidin-4-yl)-amine 2156

[B4] LCMS: Purity: >95%, RT: min, MI: 511 (M + H) 1H-NMR: DMSO 10.06 (brs, 1H), 9.84 (br m, 1H), 9.37 (br m, 1H), 9.14 (s, 1H), 8.65 (s, 1H),8.56 (s, 1H), 8.41 (d, 1H, J = 5.5 Hz), 8.28 (m, 1H), 8.06 (m, 3H), 5.50(m, 1H), 4.01 (m, 1H), 3.76-3.87 (br m, 1H), 3.45 (m, 1H), 3.35 (m, 1H),2.60 (m, 1H), 2.46 (m, 1H), 2.07 (m, 1H), 1.20 (m, 3H), 1.03 (m, 1H){5-Cyclopropyl- 2-[2-(3,5-difluoro- pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-(3,3-difluoro-piperidin-4-yl)- amine 2157

[B4] LCMS: Purity: >95%, RT: min, MI: 503 (M + H) 1H-NMR: DMSO 10.17 (brs, 1H), 9.06 (s, 1H), 8.81(br m, 1H), 8.66 (s, 1H), 8.61 (s, 1H), 8.40(d, 1H, J = 5.6 Hz), 8.35 (m, 1H), 8.29 (d, 1H, J = 2.5 Hz), 8.05 (m,1H), 7.99 (m, 1H), 4.82 (m, 1H), 4.16 (m, 1H), 3.51 (m, 1H), 3.39 (m,1H), 3.15 (m, 2H), 2.98 (s, 3H), 2.64 (m, 1H), 2.22-2.37 (br m, 4H),1.84-2.11 (br m, 5H) {5-Cyclobutyl-2-[2-(3,5- difluoro-pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-methyl-piperidin-4-yl- amine 2158

[B4] LCMS: Purity: 97%, RT: min, MI: 480.26 (MH)+ (400 MHz, d6-DMSO, δ):9.08 (s, 1H), 8.97 (br s, 2H), 8.22 (s, 1H), 8.15 (d, J = 6.5 Hz, 1H),8.09 (s, 1H), 7.71 (d, J = 6.4 Hz, 1H), 7.40-7.27 (m, 4H), 5.10 (d, J =6.6 Hz, 1H), 4.40-4.30 (m, 1H), 3.93 (br s, 4H), 3.44 (dd, J = 15.6, 7.7Hz, 1H), 3.32 (br s, 4H), 2.82 (dd, J = 15.1, 8.1 Hz, 1H), 2.70-2.63 (m,1H), 1.29-1.23 (m, 2H), 1.11-1.06 (m, 2H). trans-2-[4-(5-Cyclopropyl-4-piperazin- 1-yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-ylamino]-indan-1-ol 2159

[B4] LCMS: Purity: 98%, RT: min, MI: 468.1 (MH)+ (400 MHz, d6-DMSO, δ):9.10-8.90 (m, 3H), 8.21 (d, J = 2.7 Hz, 1H), 8.15-7.95 (m, 2H), 7.67 (d,J = 5.2 Hz, 1H), 7.47-7.27 (m, 5H), 5.04 (s, 1H), 4.10-3.65 (m, 6H),3.32 (br s, 4H), 2.70- 2.60 (m, 1H), 1.29-1.22 (m, 2H), 1.10-1.05 (m,2H). (R)-2-[4-(5- Cyclopropyl-4-piperazin- 1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-ylamino]-2-phenyl- ethanol 2160

[B4] LCMS Purity: 96%, RT: min, MI: 502.1 (MH)+ (400 MHz, d6-DMSO, δ):9.04 (s, 1H), 8.82 (br s, 2H), 8.19 (s, 1H), 8.07 (d, J = 5.7 Hz, 1H),7.95-7.87 (m, 4H), 7.62 (dd, J = 8.6, 1.7 Hz, 1H), 7.58 (br s, 1H),7.52-7.46 (m, 2H), 5.27-5.22 (m, 1H), 3.83 (br s, 4H), 3.30 (br s, 4H),2.69-2.61 (m, 1H), 1.63 (d, J = 6.7 Hz, 3H), 1.28-1.22 (m, 2H), 1.10-1.05 (m, 2H). [4-(5-Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)-pyridin- 2-yl]-((R)-1-naphthalen- 2-yl-ethyl)-amine 2161

[B4] LCMS: Purity: >90%, RT: min, MI: 484.1 (M + H) (dmso-d6) 9.13 (s,1H), 9.03 (br signal, 2H), 8.81 (s, 1H), 8.08 (d, J = 6.0 Hz, 1H), 7.89(br s, 1H), 7.62 (d, J = 6.0 Hz, 1H), 7.47 (m, 1H), 7.32 (m, 1H),7.28-7.13 (m, 2H), 5.33 (m, 1H), 4.23 (m, 1H), 3.80 (m, 4H), 3.30 (m,4H), 2.45 (m, 2H), 2.24- 2.00 (m, 3H), 1.92 (m, 1H), 1.55 (d, J = 6.8Hz, 3H) [4-(5-Cyclobutyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-[(R)- 1-(2-fluoro-phenyl)- ethyl]-amine2162

[B4] Method 5: RT: 3.11 min, MI: 508 [M + H] (500 MH, d6-DMSO) 9.68 (1H,s), 9.07 (1H, s), 8.35 (1H, d), 8.18 (1H, s), 7.97 (1H, s), 7.85 (2H,d), 7.76 (1H, d), 7.30 (2H, d), 3.92 (4H, s, broad), 3.33 (4H, s), 2.69(1H, m), 1.25 (2H, m), 1.08 (2H, m). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d] pyrimidin-2-yl)- pyridin-2-yl]-(4-trifluoromethoxy- phenyl)-amine 2163

[B4] LCMS: Purity: 95%, RT: min, MI: 521 (M + H) 1H-NMR: 9.80 (s, 1H),9.05 (s, 1H), 8.73 (m, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 8.41 (d, 1H, J =5.2 Hz), 8.30 (m, 2H), 7.95 (m, 1H), 4.79 (m, 1H), 4.16 (m, 1H), 3.50(m, 1H), 3.37 (m, 1H), 3.15 (m, 2H), 2.98 (s, 3H), 2.62 (m, 1H),2.23-2.37 (br m, 4H), 1.84-2.10 (br m, 5H) {5-Cyclobutyl-2-[2-(3,5,6-trifluoro- pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}- methyl-piperidin-4-yl- amine 2164

[B4] LCMS: Purity: 90%, RT: min, MI: 468.24 (MH)+ (400 MHz, d6-DMSO, δ):9.06 (s, 1H), 8.99 (br s, 2H), 8.21 (s, 1H), 8.12-7.95 (m, 2H), 7.67 (d,J = 6.3 Hz, 1H), 7.49-7.27 (m, 5H), 5.08- 5.00 (m, 1H), 4.10-3.65 (m,6H), 3.33 (br s, 4H), 2.70- 2.61 (m, 1H), 1.29-1.23 (m, 2H), 1.11-1.05(m, 2H). (S)-2-[5-(5- Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin- 2-ylamino]-2-phenyl- ethanol 2165

[B4] LCMS: Purity: 95%, RT: min, MI: 502.24 (MH)+ (400 MHz, d6-DMSO, δ):9.00 (s, 1H), 8.86 (br s, 2H), 8.27-8.22 (m, 1H), 8.18 (s, 1H), 8.07 (d,J = 6.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.66-7.47 (m, 4H), 5.91- 5.85(m, 1H), 3.80 (br s, 4H), 3.24 (br s, 4H), 2.66- 2.59 (m, 1H), 1.67 (d,J = 6.4 Hz, 3H), 1.27-1.21 (m, 2H), 1.09-1.04 (m, 2H).[4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4- d]pyrimidin-2-yl)-pyridin-2-yl]- ((R)-1-naphthalen-1-yl- ethyl)-amine 2166

[B4] LCMS: Purity: 96%, RT: min, MI: 488.23 (MH)+ (400 MHz, d6-DMSO, δ):9.05 (d, J = 2.2 Hz, 1H), 8.89 (br s, 2H), 8.19 (s, 1H), 8.12 (d, J =5.8 Hz, 1H), 7.85 (br s, 1H), 7.64-7.49 (m, 6H), 4.30-4.19 (m, 2H), 3.92(br s, 4H), 3.31 (br s, 4H), 2.74- 2.64 (m, 1H), 1.28-1.22 (m, 2H),1.10-1.05 (m ,2H). [4-(5-Cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2- yl]-(2,2-difluoro-2-phenyl-ethyl)-amine 2167

[B4] LCMS: Purity: 95%, RT: min, MI: 503 (M + H) 1H-NMR: DMSO 10.33 (brs, 1H), 9.00 (s, 1H), 8.71 (s, 1H), 8.50 (m, 1H), 8.41 (d, 1H, J = 5.7Hz), 8.28 (d, 1H, J = 2.5 Hz), 8.17 (s, 1H), 8.08 (m, 2H), 7.99 (m, 1H),3.30 (s, 3h), 3.16 (m, 2H), 2.80 (m, 2H), 2.38 (m, 1H), 2.19 (m, 1H),1.57 (br m, 2H), 1.29 (m, 2H), 1.03 (m, 6H) {5-Cyclopropyl-2-[2-(3,5-difluoro- pyridin-2-ylamino)- pyridin-4-yl]- pyrido[3,4-d]pyrimidin-4-yl}-methyl- piperidin-4-ylmethyl- amine 2168

[B4] LCMS: Purity: >95%, RT: min, MI: 477 (M + H) 1H-NMR: DMSO 10.17 (brs, 1H), 9.05 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 8.40 (d, 1H, J = 5.6Hz), 8.28 (d, 1H, J = 2.5 Hz), 8.06 (m, 1H), 7.98 (m, 1lH), 7.87 (m,1H), 4.53 (m, 1H), 3.95 (m, 2H), 3.53 (m, 2H), 2.61 (m, 1H), 2.13 (m,2H), 1.79 (m, 2H), 1.22 (m, 2H), 1.06 (m, 2H) {5-Cyclopropyl-2-[2-(3,5-difluoro- pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}- (tetrahydro-pyran-4-yl)- amine 2169

[B4] LCMS: Purity: 95%, RT: min, MI: 541 (M + H) 1H-NMR: DMSO 9.76 (s,1H), 8.73 (s, 1H), 8.71 (m, 1H), 8.43 (d, 1H, J = 5.2 Hz), 8.29 (m, 2H),7.95 (m, 2H), 4.87 (m, 1H), 3.45 (m, 2H), 3.10 (s, 3H), 2.98 (m, 2H),2.38 (m, 1H), 1.90- 2.28 (br m, 4H), 1.14-1.29 (br m, 2H), 0.95 (m, 2H){8-Chloro-5- cyclopropyl-2-[2-(3,5,6- trifluoro-pyridin-2-ylamino)-pyridin-4-yl]- pyrido[3,4-d] pyrimidin-4-yl}-methyl-piperidin-4-yl- amine 2170

[B4] LCMS: Purity: 95%, RT: min, MI: 523 (M + H) 1H-NMR: DMSO 10.02 (brs, 1H), 8.79 (m, 1H), 8.66 (s, 1H), 8.39 (m, 2H), 8.26 (d, 1H, J = 2.5Hz), 8.03 (m, 1H), 7.96 (2H), 4.89 (m, 1H), 3.45 (m, 2H), 3.12 (m, 2H),3.10 (s, 3H), 2.37 (m, 1H), 1.90-2.15 (br m, 4H), 1.14-1.29 (br m, 2H),0.95 (m, 2H) {8-Chloro-5- cyclopropyl-2-[2- (3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]- pyrido[3,4-d]pyrimidin- 4-yl}-methyl-piperidin-4-yl-amine 2171

[B4] LCMS: Purity: 95%, RT: min, MI: 477 (M + H) 1H-NMR: DMSO 10.16 (s,1H), 9.05-9.10 (m, 3H), 8.88 (s, 1H), 8.45 (m, 1H), 8.26 (d, 1H, J = 2.1Hz), 8.20 (s, 1H), 8.10 (m, 1H), 8.02 (m, 1H), 3.94 (m, 4H), 3.34 (m,4H), 2.69 (m, 1H), 1.27 (m, 2H), 1.09 (m, 2H) (5-Chloro-3-fluoro-pyridin-2- yl)-[4-(5-cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)- pyridin-2-yl]-amine 2172

[B4] LCMS: Purity: 95%, RT: min, MI: 490 (M + H) 1H-NMR: DMSO 10.48 (brs, 1H), 8.99 (s, 1H), 8.65 (s, 1H), 8.41 (d, 1H, J = 5.8 Hz), 8.30 (d,1H, J = 2.4 Hz), 8.18 (s, 1H), 8.09 (m, 1H), 7.98 (m, 1H), 4.81 (m, 1H),3.97 (m, 2H), 3.48 (m, 2H), 3.15 (s, 3H), 2.40 (m, 1H), 1.75-2.07 (br m,4H), 1.23 (m, 2H), 0.98 (m, 2H) {5-Cyclopropyl- 2-[2-(3,5-difluoro-pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-methyl-(tetrahydro- pyran-4-yl)-amine 2173

[B4] LCMS: Purity: 95%, RT: min, MI: 530 (M + H) 1H-NMR: DMSO 10.73 (brs, 1H), 8.94 (s, 1H), 8.71 (s, 1H), 8.42 (d, 1H, J = 5.9 Hz), 8.29 (d,1H, J = 2.5 Hz), 8.19 (s, 1H), 8.13 (m, 1H), 8.04 (m, 1H), 4.03 (m, 1H),3.84 (m, 4H), 3.67 (m, 1H), 3.29 (m, 2H), 2.28 (m, 1H), 2.11 (m, 1H),1.98 (m, 1H), 1.53 (m ,4H), 1.16- 1.37 (br m, 4H), 1.03 (m, 1H), 0.94(m, 1H) (4-{5-Cyclopropyl-4-[3- (tetrahydro-pyran-4-yl)-pyrrolidin-1-yl]- pyrido[3,4-d]pyrimidin- 2-yl}-pyridin-2-yl)-(3,5-difluoro-pyridin- 2-yl)-amine 2174

[B4] LCMS: Purity: 95%, RT: min, MI: 489 (M + H) 1H-NMR: DMSO 10.09 (s,1H), 9.08 (s, 1H), 8.73 (s, 1H), 8.59 (m, 1H), 8.53 (s, 1H), 8.50 (m,1H), 8.41 (d, 1H, J = 5.5 Hz), 8.24 (d, 1H, J = 2.5 Hz), 8.05 (m, 1H),7.95 (m, 1H), 7.69 (s, 1H), 3.24 (m, 2H), 3.17 (m, 2H), 2.74 (m, 2H),2.64 (m, 1H), 2.06 (m, 2H), 1.75 (s, 3H), 1.22 (m, 2H), 1.16 (m, 2H){5-Cylcopropyl- 2-[2-(3,5-difluoro- pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-(4- methyl-piperidin-4-yl)-amine 2175

[B4] LCMS: Purity: 95%, RT: min, MI: 503 (M + H) 1H-NMR: DMSO 10.15 (brs, 1H), 9.09 (s, 1H), 9.07 (m, 1H), 8.63 (s, 1H), 8.52 (s, 1H), 8.41 (d,1H, J = 5.6 Hz), 8.35 (m, 1H), 8.27 (d, 1H, J = 2.5 Hz), 8.05 (m, 2H),7.67 (d, 1H, J = 8.7 Hz), 4.82 (m, 1H), 3.37 (m, 1H), 3.20 (m, 2H), 3.06(m, 1H), 2.60 (m, 1H), 2.12 (m, 1H), 1.96 (m, 1H), 1.26 (m, 1H), 1.19(s, 3H), 1.16 (m, 3H), 1.11 (s, 3H) {5-Cyclopropyl- 2-[2-(3,5-difluoro-pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-(3,3-dimethyl-piperidin-4-yl)- amine 2176

[B4] LCMS: Purity: 95%, RT: min, MI: 521 (M + H) 1H-NMR: DMSO 9.72 (s,1H), 9.06 (s, 1H), 8.99 (m, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 8.40 (m,1H), 8.27 (m, 2H), 8.00 (m, 1H), 7.64 (d, 1H, J = 8.8 Hz), 4.81 (m, 1H),3.32 (m, 1H), 3.22 (m, 1H), 3.19 (m, 1H), 3.01 (m, 1H), 2.59 (m, 1H),2.14 (m, 1H), 1.95 (m, 1H), 1.25 (m, 1H), 1.19 (s, 3H), 1.14 (m, 3H),1.09 (s, 3H) {5-Cylcopropyl- 2-[2-(3,5,6-trifluoro- pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-(3,3-dimethyl-piperidin-4-yl)- amine 2177

[B4] LCMS: Purity: 92%, RT: min, MI: 492.26 (MH)+ (400 MHz, d6-DMSO, δ):9.06 (s, 1H), 8.85 (br s, 2H), 8.20 (s, 1H), 8.16 (d, J = 6.0 Hz, 1H),7.61 (br s, 1H), 7.34-7.20 (m, 4H), 5.62- 5.55 (m, 1H), 3.88 (br s, 4H),3.31 (br s, 4H), 2.70- 2.63 (m, 1H), 1.85-1.79 (m, 1H), 1.40 (s, 3H),1.28-1.23 (m, 6H), 1.11-1.06 (m, 2H). [4-(5-Cyclopropyl-4-piperazin-1-yl- pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]-(3,3-dimethyl-indan- 1-yl)-amine 2178

[B4] LCMS: Purity: 99%, RT: min, MI: 513 (M + H) 1H NMR (400 MHz,DMSO-d6) 9.79 (1 H, s), 8.65-9.06 (3 H, m), 8.41- 8.51 (1 H, m),8.20-8.36 (1 H, m), 7.90-8.04 (2 H, m), 3.98 (4 H, br. s.), 3.30 (4 H,br. s.), 2.56-2.65 (1 H, m), 1.19-1.28 (2 H, m), 1.00- 1.10 (2 H, m)[4-(8-Chloro- 5-cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]- (3,5,6,-trifluoro- pyridin-2-yl)-amine 2179

[D4], [D3] LCMS: Purity: 96%, RT: min, MI: 467.21 (dmso-d6) 12.45 (d, J= 1.4 Hz, 1H), 9.13 (s, 1H), 8.96 (br s, 2H), 8.62 (m, 1H), 8.51 (d, J =5.0 Hz, 1H), 8.20 (m, 3H), 7.93 (m, 1H), 7.53 (m, 1H), 3.98 (br s, 4H),3.38 (br s, 4H), 2.76 (m, 1H), 1.28 (m, 2H), 1.11 (m, 2H)5-Cyclopropyl-2- [2-(3-fluoro- pyridin-2-yl)-1H- pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin- 1-yl-pyrido[3,4- d]pyrimidine 2180

[D4], [D3] LCMS: Purity: 96%, RT: min, MI: 481.22 (M + H) (dmso-d6)12.45 (d, J = 1.5 Hz, 1H), 9.20 (s, 1H), 8.99 (br s, 1H), 8.89 (br s,1H), 8.81 (s, 1H), 8.61 (m, 1H), 8.51 (d, J = 5.0 Hz, 1H), 8.19 (d, J =5.0 Hz, 1H), 8.17 (m, 1H), 7.93 (m, 1H), 7.53 (m, 1H), 4.30 (m, 1H),3.87 (m, 4H), 3.35 (m, 4H), 2.47 (m, 2H), 2.24 (m, 2H), 2.12 (m, 1H),1.93 (m, 1H) 5-Cyclobutyl- 2-[2-(3-fluoro-pyridin- 2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidine 2181

[D4], [D3] Method 5: RT: 3.27 min, MI: 516 [M + H] (500 MHz, d6-DMSO)11.86 (brs, 1H), 9.19 (s, 1H), 8.97 (brs, 1H), 8.82 (brs, 1H), 8.77 (s,1H), 8.28 (d, 1H), 8.06 (d, 1H), 7.53- 7.40 (m, 2H), 7.38-7.30 (m, 2H),7.25-7.15 (m, 2H), 4.27 (q, 1H), 3.90-3.56 (m, 5H), 3.40-3.20 (m, 4H),3.08 (m, 1H), 2.97-2.85 (m, 2H), 2.78-2.67 (m, 2H), 2.27-2.16 (m, 2H),2.15- 2.03 (m, 2H), 1.95-1.87 (m, 2H). 5-Cyclobutyl-2-[2-(1-phenyl-cyclobutyl)- 1H-pyrrolo[2,3- b]pyridin-4-yl]-4-piperazin-1-yl- pyrido[3,4-d]pyrimidine 2182

[D4], [D3] Method 5: RT: 2.98 min, MI: 496 [M + H] (500 MHz, d6-DMSO)12.11 (brs, 1H), 9.25 (s, 1H), 9.07 (brs, 1H), 8.92 (brs, 1H), 8.79 (s,1H), 8.43 (d, 1H), 8.12 (d, 1H), 7.46 (d, 1H), 4.28 (q, 1H), 3.99- 3.70(m, 4H), 3.45-3.20 (m, 4H), 2.52-2.42 (m, 2H), 2.28-2.16 (m, 2H), 2.10(m, 1H), 1.92 (m, 1H), 1.69 (s, 6H). 5-Cyclobutyl-4-piperazin-1-yl-2-[2- (2,2,2-trifluoro-1,1- dimethyl-ethyl)-1H-pyrrolo[2,3- b]pyridin- 4-yl]-pyrido [3,4-d]pyrimidine 2183

[D4], [D3] Method 5: RT: 3.06 min, MI: 508 [M + H] (d6-DMSO, 600 MHz)12.20 (brs, 1H), 9.25 (s, 1H), 8.98 (brs, 1H), 8.84 (brs, 1h), 8.80 (s,1H), 8.43 (d, 1H), 8.14 (d, 1H), 7.49 (d, 1H), 4.29 (q, 1H), 3.98-3.71(m, 4H), 3.46-3.21 (m, 4H), 2.84-2.59 (m, 4H), 2.50- 2.41 (m, 2H),2.30-2.18 (m, 2H), 2.18-2.00 (m, 3H), 1.93 (m, 1H). 5-Cyclobutyl-4-piperazin-1-yl-2-[2- (1-trifluoromethyl- cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-4- yl]-pyrido[3,4- d]pyrimidine 2184

[D4], [D3] Method 5: RT: 5.02 min, MI: 456 [M + H] (500 MHz, d6-DMSO)11.80 (1H, s), 9.05 (1H, s), 8.29 (1H, d, J = 5.0 Hz), 8.08 (1H, s),8.06 (1H, d, J = 5.0 Hz), 7.28 (1H, d, J = 1.3 Hz), 4.13 (1H, t, J = 7.6Hz), 3.98-3.93 (1H, m), 8.89-8.84 (1H, m), 3.80- 3.77 (1H, t, J = 7.7Hz), 3.68-3.61 (1H, m), 3.92- 3.50 (4H, very broad s), 2.89 (4H, s),2.71-2.65 (1H, m), 2.42-2.35 (1H, m), 2.21- 2.14 (1H, m), 1.28-1.245-Cyclobutyl- 4-piperazin-1-yl-2-[2- (tetrahydro-furan-3-yl)-1H-pyrrolo[2,3-b] pyridin-4-yl]-pyrido[3,4- d]pyrimidine (2H, m),1.05-1.02 (2H, m). 2185

[D4], [D3] Method 5: RT: 2.51 min, MI: 456 [M + H] (500 MHz, d6-DMSO)11.82 (1H, s), 9.13 (1H, s), 8.70 (1H, s), 8.32 (1H, d, J = 4.9 Hz),8.06 (1H, d, J = 4.9 Hz), 7.33 (1H, d, J = 1.7 Hz), 5.09 (1H, t, J = 6.8Hz), 4.32-4.25 (1H, m), 4.03-3.98 (1H, m) 3.87- 3.82 (1H, m), 3.68 (2H,br s), 3.51 (2H, br s), 2.94 (2H, br s), 2.87 (2H, br s), 2.38- 2.28(1H, m), 2.23-2.15 (2H, m), 2.12-1.96 (5H, m), 1.93-1.89 (1H, m).5-Cyclobutyl-4- piperazin-1-yl-2-[2- (tetrahydro-furan-2-yl)-1H-pyrrolo[2,3-b] pyridin-4-yl]-pyrido[3,4- d]pyrimidine 2186

[B4] LCMS: Purity: 95% RT: min, MI: 493 (M + H) 1H-NMR: DMSO 9.97 (br s,1H), 9.21 (m, 1H), 9.12 (s, 1H), 8.79 (m, 1H), 8.62 (s, 1H), 8.54 (s,1H), 8.39 (d, 1H, J = 5.5 Hz), 8.28 (d, 1H, J = 2.5 Hz), 8.02 (m, 3H),5.37-5.44 (br m, 1H), 4.85-4.96 (br m, 1H), 3.77 (m, 1H), 3.40-3.63 (brm, 2H), 3.27 (m, 1H), 2.59 (m, 1H), 2.33 (m, 1H), 2.07 (m, 1H), 1.21 (m,2H), 1.13 (m, 2H) {5-Cyclopropyl- 2-[2-(3,5-difluoro-pyridin-2-ylamino)- pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-(3-fluoro-piperidin-4-yl)- amine 2187

[B4] LCMS: Purity: 95%, RT: min, MI: 519 (M + H) 1H NMR (400 MHz,DMSO-d6) 9.76 (1H, s), 9.05 (1H, s), 8.86 (2H, br. s), 8.46 (1H, d, J =5.0 Hz), 8.20-8.35 (1H, m), 7.95- 8.05 (2H, m), 3.74-4.06 (4H, m),3.49-3.63 (1H, m), 3.31 (4H, br. s.), 2.57- 2.70 (1H, m), 1.05-1.25 (6H,m), 0.90-1.03 (2H, m) [4-(5,8- Dicyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2- yl]-(3,5,6-trifluoro-pyridin-2-yl)-amine 2188

[B4] LCMS: Purity: 90%, RT: min, MI: 501 (M + H) 1H NMR (400 Mhz,DMSO-d6) 9.84 (1H, br. s), 8.63-9.04 (3H, m), 8.41 (1H, d, J = 5.0 Hz),8.25 (1H, d, J = 2.5 Hz), 7.92-8.09 (3H, m), 3.90 (4H, br. s), 3.47-3.58(1H, m), 3.32 (4H, br. s), 2.57-2.65 (1H, m), 1.05-1.26 (6H, m),0.90-1.00 (2H, m) [4-(5,8- Dicyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2- yl]-(3,5-difluoro-pyridin-2-yl)-amine 2189

[B4] LCMS: Purity: 90%, RT: min, MI: 500 (M + H) 1H NMR (400 MHz,DMSO-d6) 8.83 (2H, s), 8.19 (1H, d, J = 5.3 Hz), 8.00 (1H, s), 7.88 (1H,s), 7.73 (1H, dd, J = 5.4, 1.4 Hz), 7.23- 7.34 (1H, m), 7.11-7.21 (2H,m), 3.85-3.96 (4H, m), 3.46-3.49 (1H, m), 3.30 (4H, br. s), 2.57-2.65(1H, m), 1.05-1.23 (6H, m), 0.96 (2H, m) [4-(5,8- Dicyclopropyl-4-piperazin-1-yl- pyrido[3,4-d]pyrimidin- 2-yl)-pyridin-2-yl]-(2,6-difluoro-phenyl)- amine 2190

[D4], [D3] LCMS: Purity: 95%, RT: min, MI: 468 (M + H) 1H NMR (400 MHz,DMSO-d6) 11.80 (1H, d, J = 1.8 Hz), 8.48-9.20 (2H, m), 8.32 (1H, d, J =5.0 Hz), 8.12 (1H, d, J = 5.0 Hz), 8.00 (1H, s), 7.24 (1H, d, J = 2.3Hz), 3.71-4.20 (4H, m), 3.47-3.59 (1H, m), 3.34 (4H, br. s), 2.63-2.76(1H, m), 1.41 (9H, s), 1.10-1.28 (6H, m), 0.89-1.00 (2H, m)2-(2-tert-Butyl-1H- pyrrolo[2,3- b]pyridin- 4-yl)-5,8-dicyclopropyl-4-piperazin-1-yl-pyrido [3,4-d]pyrimidine 2191

[B4] Method 5: RT: 1.86 min, MI: 444 [M + H] (500 MHz, DMSO) 9.08 (1H,s), 9.07 (1H, s), 8.76 (1H, s), 8.46 (1H, d), 8.35 (1H, m), 8.19 (1H,s), 7.93 (1H, dd), 7.63 (1H, dd), 7.43 (2H, dd), 7.17 (2H, m), 3.95 (4H,br s), 3.33 (4H, s), 2.69 (1H, m), 1.25 (2H, m), 1.09 (2H, m).[4-(5-Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d] pyrimidin-2-yl)-pyridin-2-yl]-(6- fluoro-pyridazin-3-yl)- amine 2192

[D4], [D3] Method 5: RT: 3.08 min, MI: 442 [M + H] (500 MHz, d6-DMSO)11.80 (1H, s), 9.05 (1H, s), 8.29 (1H, d, J = 5.0 Hz), 8.08 (1H, s),8.06 (1H, d, J = 5.0 Hz), 7.28 (1H, d, J = 1.3 Hz), 4.13 (1H, t, J = 7.6Hz), 3.98-3.93 (1H, m), 8.89-8.84 (1H, m), 3.80- 3.77 (1H, t, J = 7.7Hz), 3.68-3.61 (1H, m), 3.92- 3.50 (4H very broad s), 2.89 (4H, s),2.71-2.65 (1H, m), 5-Cyclopropyl-4- piperazin-1-yl-2-[2-(tetrahydro-furan-3- yl)-1H-pyrrolo[2,3-b] pyridin-4-yl]-pyrido[3,4-d]pyrimidine 2.42-2.35 (1H, m), 2.21- 2.14 (1H, m), 1.28-1.24 (2H,m), 1.05-1.02 (2H, m). 2193

[B1] LCMS: Purity: 90%, RT: min, MI: 488 (M + H)+ 1H NMR (400 MHz,DMSO-d6) δ ppm 9.55 (br. s, 1H) 9.05 (br. s, 1H) 8.79- 8.87 (m, 2H) 8.21(d, J = 5.3 Hz, 1H) 7.82 (s, 1H) 7.69 (dd, J = 5.3, 1.3 Hz, 1H)7.23-7.35 (m, 1H) 7.10-7.22 (m, 2H) 3.51-4.03 (m, 9H)(2,6-Difluoro-phenyl)- [4-(4-piperazin-1-yl-5- trifluoromethyl-pyrido[3,4-d] pyrimidin-2-yl)-pyridin- 2-yl]-amine 2194

[B1] LCMS: Purity: 90%, RT: min, MI: 489 (M + H)+ 1H NMR (400 MHz,DMSO-d6) δ ppm 9.65- 9.72 (m, 1H) 9.58 (s, 1H) 9.06 (s, 1H) 8.80-8.98(m, 2H) 8.76 (br. s, 1H) 8.38- 8.47 (m, 1H) 8.27 (br. s, 1H) 7.99 (t, J= 8.4 Hz, 1H) 7.87-7.94 (m, 1H) 3.70- 4.04 (m, 8H)(3,5-Difluoro-pyridin-2- yl)-[4-(4-piperazin- 1-yl-5-trifluoromethyl-pyrido[3,4-d] pyrimidin-2-yl)-pyridin- 2-yl]-amine 2195

[B1] LCMS: Purity: 90%, RT: min, MI: 507 (M + H)+ 1H NMR (400 MHz,DMSO-d6) δ ppm 9.79- 9.83 (m, 1H) 9.56 (s, 1H) 9.04-9.07 (m, 1H) 8.82-8.93 (m, 2H) 8.78-8.81 (m, 1H) 8.47 (d, J = 5.0 Hz, 1 H) 8.23-8.33 (m,1H) 7.96 (dd, J = 5.3, 1.5 Hz, 1H) 3.70-4.12 (m, 9H)[4-(4-Piperazin-1-yl-5- trifluoromethyl-pyrido [3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5,6- trifluoro-pyridin-2- yl)-amine 2196

[B4] LCMS: Purity: 95%, RT: min, MI: 517 (M + H) 1H-NMR: DMSO 10.42 (brs, 1H), 9.14 (br m, 1H), 9.01 (s, 1H), 8.61 (br m, 1H), 8.41 (d, 1H, J =5.7 Hz), 8.30 (br m, 1H), 8.28 (d, 1H, J = 2.4 Hz), 8.16 (s, 1H), 8.07(m, 2H), 5.56 (m, 1H), 3.45 (m, 1H), 3.30 (m, 2H), 3.16 (s, 3H), 2.78(m, 1H), 2.41 (m, 1H), 2.22 (m, 1H), 1.91 (m, 1H), 0.98- 1.47 (br m,10H) {5-Cyclopropyl- 2-[2-(3,5-difluoro- pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-(3,3-dimethyl-piperidin-4-yl)- methyl-amine 2197

[D3] LCMS: Purity: 90%, RT: min, MI: 402 (M + H)+ NH protons coalescedwith water. 1H NMR (400 MHz, CDCl₃) δ ppm 9.10 (s, 1H) 8.04 (s, 1H) 7.95(d, J = 4.5 Hz, 1H) 7.53 (d, J = 5.5 Hz, 1H) 7.27 (s, 1H) 4.83 (br. s,1H) 3.54-3.92 (m, 4H), 3.48 (s, 2H) 3.04 (t, J = 4.8 Hz, 4H) 2.73 (tt, J= 8.5, 5.2 Hz, 1H) 1.40 (s, 6H) 0.98- 1.05 (m, 2H) 0.85-0.91 (m, 2H)5-Cyclopropyl-2-(2,2- dimethyl-2,3-dihydro- 1H-pyrrolo[2,3-b]pyridin-4-yl)-4- piperazin-1-yl-pyrido [3,4-d]pyrimidine 2198

[B4] LCMS: LPurity: 95%, RT: min, MI: 475 (M + H) 1H-NMR: DMSO 10.23 (brs, 1H), 9.05 (s, 1H), 8.73 (s, 1H), 8.42 (d, 1H, J = 5.6 Hz), 8.29 (d,1H, J = 2.4 Hz), 8.19 (s, 1H) , 8.08 (br m, 4H), 4.44 (m, 1H), 4.07-4.23 (br m, 2H), 3.22-3.47 (br m, 3H), 2.67 (m ,1H), 2.07 (m, 1H), 1.84(m, 1H), 1.61 (m, 1H), 1.26 (m, 2H), 1.05 (m, 2H) {4-[4-(3-Amino-piperidin-1-yl)-5- cyclopropyl-pyrido[3,4- d]pyrimidin-2-yl]- pyridin-2-yl}-(3,5-difluoro- pyridin-2-yl)-amine 2199

[D3], [D9] Method 5: RT: 3.31 min, MI: 440 [M + H] (500 MHz, d6-DMSO)11.59 (brs, 1H), 9.15 (s, 1H), 9.04 (brs, 1H), 8.91 (brs, 1H), 8.79 (s,1H), 8.11 (d, 1H), 7.58 (d, 1H), 4.32- 4.21 (m, 1H), 3.89-3.63 (m, 4H),3.39-3.19 (m, 4H), 2.78-2.70 (m, 2H), 2.64- 2.52 (m, 2H), 2.28-2.16 (m,2H), 2.15-2.02 (m, 1H), 1.97-1.87 (m, 1H), 1.85- 1.72 (m, 2H), 1.70-1.54(m, 2H). 4-(5-Cyclobutyl- 4-piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)-6,7,8,9-tetrahydro- 5H-pyrido[2,3-b]indole 2200

[D3] LCMS: Purity: 98%, RT: min, MI: 470 (M + H) 1H-NMR (DMSO-d6, 400MHz): 12.30 (s, 1H), 9.22 (s, 1H), 9.06 (d, 1H, J = 2.1 Hz), 8.90 (br s,2H), 8.86 (s, 1H), 8.65 (d, 1H, J = 5.1 Hz), 8.03 (5.1 Hz), 7.58 (d, 1H,J = 8.6 Hz), 7.54 (dd, 1H, J = 2.1, 8.6 Hz), 4.30 (pent, 1H, J = 8.6Hz), 3.86 (m, 4H), 3.2-3.4 (m, 4H), 2.28 (m, 2H), 2.14 (m, 1H), 1.94 (m,1H) 6-Chloro-4-(5- cyclobutyl-4-piperazin- 1-yl-pyrido[3,4-d]pyrimidin-2-yl)-9H- pyrido[2,3-b]indole 2201

[D4], [D3] LCMS: Purity: 95%, RT: min, MI: 410.0 (MH)+ (dmso-d6) 12.40(d, J = 1.7 Hz, 1H), 9.14 (s, 1H), 8.95 (br s, 2H), 8.46 (d, J = 5.0 Hz,1H), 8.18 (m, 2H), 8.10 (m, 1H), 7.98 (m, 1H), 7.52- 7.35 (m, 3H), 3.98(br s, 4H), 3.38 (br s, 4H), 2.76 (m, 1H), 1.27 (m, 2H), 1.10 (m, 2H)5-Cyclopropyl-2-[2- (2-fluoro-phenyl)-1H- pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin- 1-yl-pyrido[3,4- d]pyrimidine 2202

[D4], [D3] LCMS: Purity: 95%, RT: min, MI: 466.22 (M + H) (dmso-d6)12.32 (d, J = 1.7 Hz, 1H), 9.14 (s, 1H), 8.94 (br s, 2H), 8.47 (d, J =5.0 Hz, 1H), 8.19 (d, J = 5.0 Hz, 1H), 8.19 (s, 1H), 7.94 (d, J = 2.2Hz, 1H), 7.85 (dd, J = 7.7, 1.7 Hz, 1H), 7.67 (dd, J = 7.8, 1.4 Hz, 1H),7.55- 7.45 (m, 2H), 3.96 (br s, 4H), 3.37 (br s, 4H), 2.76 (m, 1H), 1.27(m, 2H), 1.10 (m, 2H) 2-[2-(2-Chloro- phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]- 5-cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidine 2203

[D4], [D3] LCMS: Purity: 97%, RT: min, MI: 482.18 (M + H) (dmso-d6)12.40 (s, 1H), 9.22 (s, 1H), 9.00 (br s, 1H), 8.89 (br s, 1H), 8.80 (s,1H), 8.46 (d, J = 5.0 Hz, 1H), 8.17 (d, J = 5.0 Hz, 1H), 8.10 (m, 1H),7.96 (m, 1H), 7.52-7.36 (m, 3H), 4.30 (m, 1H), 3.87 (m, 4H), 3.35 (m,4H), 2.48 (m, 2H), 2.24 (m, 2H), 2.11 (m, 1H), 1.93 (m, 1H)5-Cyclobutyl- 2-[2-(2-fluoro-phenyl)- 1H-pyrrolo[2,3-b] pyridin-4-yl]-4-piperazin- 1-yl-pyrido[3,4-d] pyrimidine 2204

[D4], [D3] LCMS: Purity: 97%, RT: min, MI: 480.22 (M + H) (dmso-d6)12.32 (d, J = 1.7 Hz, 1H), 9.22 (s, 1H), 8.98 (br s, 1H), 8.85 (br s,1H), 8.80 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.18 (d, J = 5.0 Hz, 1H),7.92 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 7.6, 1.8 Hz, 1H), 7.67 (dd, J=7.9, 1.6 Hz, 1H), 7.56-7.44 (m, 2H), 4.30 (m, 1H), 3.84 (m, 4H), 3.34(m, 4H), 2.47 (m, 2H), 2.24 (m, 2H), 2.11 (m, 1H), 1.93 (m, 1H)2-[2-(2-Chloro- phenyl)-1H-pyrrolo [2,3-b]pyridin-4-yl]- 5-cyclobutyl-4-piperazin-1-yl- pyrido[3,4-d]pyrimidine 2205

[B4] LCMS: Purity: 95%, RT: min, MI: 489 (M + H) 1H-NMR: DMSO 10.08 (brs, 1H), 9.05 (s, 1H), 8.70 (br m, 3H), 8.40 (d, 1H, J = 5.5 Hz), 8.29(d, 1H, J = 2.2 Hz), 8.18 (s, 1H), 8.00 (m, 2H), 4.56 (br m, 1H), 4.18(br m, 1H), 3.50 (m, 2H), 3.16 (m, 1H), 2.63 (s, 3H), 2.54 (m, 1H), 2.12(m, 1H), 1.82 (m, 1H), 1.64 (m, 2H), 1.25 (m, 2H), 1.05 (m, 2H){4-[5-Cyclopropyl- 4-(3-methylamino- piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]- pyridin-2-yl}-(3,5- difluoro-pyridin-2-yl)-amine 2206

[B4] LCMS: Purity: 95%, RT: min, MI: 497 (M + H) 1H-NMR: DMSO 10.38 (brs, 1H), 9.66 (s, 1H), 9.09 (s, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 8.43 (d,1H, J = 5.7 Hz), 8.22 (d, 1H, J = 2.5 Hz), 8.10 (m, 1H), 7.94 (m, 1H),7.76 (m, 2H), 6.77 (m, 2H), 2.79 (m, 1H), 2.76 (s, 3H), 1.30 (m, 2H),1.14 (m, 2H) N-{5-Cyclopropyl- 2-[2-(3,5-difluoro- pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4- d]pyrimidin-4-yl}-N′- methyl-benzene-1,4-diamine 2207

[D4], [D3] Method 5: RT: 2.87 min, MI: 494 [M + H] (500 MHz, d6-DMSO)12.17 (brs, 1H), 9.17 (s, 1H), 8.89 (brs, 2H), 8.42 (t, 1H), 8.17 (d,1H), 8.14 (t, 1H), 7.49 (s, 1H), 4.21-3.56 (m, 6H), 2.82-2.64 (m, 6H),2.17-1.98 (m, 3H), 1.34- 1.20 (m, 2H), 1.14-1.03 (m, 2H). 5-Cyclopropyl-4-piperazin-1-yl-2-[2- (1-trifluoromethyl- cyclobutyl)-1H-pyrrolo[2,3-b]pyridin- 4-yl]-pyrido[3,4- d]pyrimidine 2208

[D3], [D9] Method 5: RT: 2.88 min, MI: 426 [M + H] (500 MHz, d6-DMSO)11.53 (s, 1H), 9.06 (s, 1H), 8.21 (d, 1H), 8.17 (s, 1H), 7.56 (d, 1H),4.09-3.61 (m, 4H), 3.35-3.28 (m, 4H), 2.78-2.68 (m, 3H), 2.64- 2.58 (m,2H), 1.85-1.77 (m, 2H), 1.69-1.61 (m, 2H), 1.30-1.23 (m, 2H), 1.12- 1.07(m, 2H). 4-(5-Cyclopropyl-4- piperazin-1-yl- pyrido[3,4-d]pyrimidin-2-yl)-6,7,8,9- tetrahydro-5H-pyrido [2,3-b]indole 2209

[D4], [D3], [D7] Method 5: RT: 3.45 min, MI: 474 [M + H] (500 MHz,d6-DMSO) 8.96 (1H, s), 8.59 (1H, d), 8.13 (1H, s), 7.57 (1H, d), 3.89-3.46 (4H, m), 2.84 (4H, s), 2.71-2.59 (1H, m), 1.29- 1.24 (2H, m),1.06-1.01 (2H, m). 2-(3-Chloro- 2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)- 5-cyclopropyl-4- piperazin-1-yl-pyrido[3,4-d]pyrimidine 2210

[B4] Method 5: RT: 1.44 min, MI: 446 [M + H] (500 MHz, DMSO) 9.07 (1H,s), 8.74 (1H, s), 8.12 (1H, d), 7.54 (1H, s), 7.42 (1H, dd), 6.79 (1H,d), 4.24 (1H, m), 3.98 (1H, m), 3.89 (2H, m), 3.78-3.67 (4H, m), 3.42(2H, m), 3.19 (2H, m), 3.09 (2H, m), 2.46 (2H, m), 2.19 (2H, m), 2.09(1H, m), 1.90 (3H, m), 1.46 (2H, m). [4-(5-Cyclobutyl-4- piperazin-1-yl-pyrido[3,4-d] pyrimidin-2-yl)- pyridin-2-yl]- (tetrahydro-pyran-4-yl)-amine 2211

[D3], [D10] Method 5: RT: 2.71 min, MI: 416 [M + H] (300 MHz, DMSO-d6) d11.20 (s, 1H), 9.08 (s, 1H), 8.94 (bs, 2H), 8.25 (d, J = 5.5 Hz, 1H),8.21 (s, 1H), 7.80 (d, J = 5.5 Hz, 1H), 3.86 (bs, 4H), 3.32 (bs, 4H),2.73-2.64 (m, 1H), 1.55 (s, 6H), 1.31-1.19 (m, 2H), 1.14-1.04 (m, 2H)4-(5-Cyclopropyl-4- piperazin-1-yl- pyrido[3,4- d]pyrimidin-2-yl)-3,3-dimethyl-1,3-dihydro- pyrrolo[2,3- b] pyridin-2-one

VI. Biology

PKCL IC₅₀, Assay

Assays are based on the ability of PKCι to phosphorylate a commerciallyavailable peptide substrate in vitro. The peptide substrate is FAM-PKCεpseudopeptide derived peptide, and comprises the amino acid sequence5FAM-ERMRPRKRQGSVRRRV-NH₂. Recombinant, full-length human PKCι expressedin Sf21 insect cells is also commercially available. Recombinant,kinase-domain human PKCι is expressed and purified in-house.

The procedure below explains how dose response curves for inhibitors ofPKCι are obtained. The screen described is for a 384 well format but theassay can be adapted to 1536 or other formats as required.

Compounds to be tested are dissolved in 100% DMSO. Compounds are dilutedas required to give a final concentration of 4% DMSO (v/v) in the assay.1 μl is plated into 384 well black low-binding flat bottomed assayplates which are used immediately. Dilutions and additions of compoundto assay plates are carried out using Matrix WellMate and MatrixPlateMate® Plus liquid handling systems.

On the day of the screen PKCι/substrate working solution, and ATPworking solution, are prepared in buffer containing 20 mM tris-HClpH7.5, 10 mM MgCl₂, 0.01% Triton X100, 250 μM EGTA and 1 mM DTT. Thefinal concentration of PKCι used varies depending on the batch ofprotein but is typically 15 pM. The final concentration of peptidesubstrate in the assay is 100 nM. ATP is used at a final concentrationof 150 μM or 25 μM in the assays containing full-length or kinase-domainPKCι respectively, which corresponds to five times or equal to the K_(M)^(APP) for ATP for each enzyme, respectively. The final bufferconcentration in the assay is 18 mM tris-HCl pH7.5, 9 mM MgCl₂, 0.009%Triton X100, 225 μM EGTA and 0.9 mM DTT. Relevant controls are included,namely no compound and no enzyme. 5 μl PKCι/substrate working solutionat 30 pM and 200 nM, respectively, is added to the wells, followed by 4μl ATP working solution at 375 μM or 62.5 μM for full-length orkinase-domain PKCι respectively, using a 16 channel Matrix pipette. Thereaction is allowed to incubate for 60 minutes at room temperature,before the reaction is stopped and developed by the addition of 20 μlIMAP™ development reagent (Molecular Devices). IMAP development reagentconsists of 0.25% (v/v) IMAP progressive binding reagent, 17% (v/v) IMAPprogressive binding buffer A and 3% (v/v) IMAP progressive bindingbuffer B. The plates are then incubated for 2 hours at room temperaturebefore being read using an appropriate plate reader, for example aMolecular Devices HT Analyst or a BMG Pherastar. Plates are read using afluorescence polarisation protocol with excitation at 485 nm andemission at 530 nm, and dichroic mirror at 505 nm.

Percentage inhibition values are calculated from fluorescencepolarisation values, using the no compound and no enzyme control valuesas 0% and 100% inhibition, respectively. IC50 determination is performedwith ExcelFit software (IDBS) using curve fit 205. Z′ factors aredetermined for each plate tested and are all above 0.5.

RESULTS

Biological data for the Example compounds is presented in the followingtable. Activities are set forth as follows:

IC50 in IMAP assay against full length PKCi at 150 μM ATP:

-   -   ++++=<100 nM    -   +++=100 nM to 1,000 nM    -   ++=1,000 nM to 10,000 nM    -   +=10,000 nM to 40,000 nM

Example Activity 1 +++ 2 +++ 3 + 4 ++ 5 + 6 ++++ 7 ++++ 8 +++ 9 ++++ 10+++ 11 ++++ 12 ++++ 13 ++ 14 +++ 15 ++ 16 +++ 17 ++ 18 + 19 + 20 + 21 +22 + 23 + 24 + 25 +++ 26 + 27 + 28 +++ 29 ++ 30 ++ 31 +++ 32 +++ 33 ++34 + 35 + 36 + 37 ++++ 38 +++ 39 + 40 ++ 41 ++++ 42 + 43 ++ 44 +++ 45 ++46 ++++ 47 ++++ 48 ++ 49 ++ 50 + 51 ++ 52 ++ 53 +++ 54 ++ 55 ++ 56 +57 + 58 +++ 59 + 60 ++ 61 ++ 62 ++ 63 +++ 64 + 65 + 66 + 67 + 68 +++69 + 70 ++ 71 ++ 72 ++ 73 + 74 ++++ 75 ++ 76 ++++ 77 ++++ 78 ++ 79 + 80+++ 81 +++ 82 ++ 83 + 84 + 85 + 86 ++ 87 + 88 +++ 89 ++++ 90 +++ 91 +++92 ++ 93 +++ 94 +++ 95 +++ 96 +++ 97 +++ 98 ++ 99 +++ 100 +++ 101 ++ 102+++ 103 +++ 104 ++ 105 ++++ 106 ++ 107 ++ 108 +++ 109 +++ 110 +++ 111+++ 112 + 113 +++ 114 +++ 115 ++++ 116 ++ 117 ++ 118 ++ 119 ++ 120 ++121 +++ 122 +++ 123 ++ 124 ++ 125 ++ 126 +++ 127 + 128 ++ 129 +++ 130 ++131 ++++ 132 ++++ 133 ++++ 134 ++++ 135 ++++ 136 ++++ 137 ++++ 138 ++++139 ++++ 140 +++ 141 +++ 142 ++ 143 ++++ 151 +++ 152 ++ 153 ++ 154 +++155 ++ 156 ++ 157 ++ 158 ++ 159 + 160 + 200 ++++ 201 ++++ 202 ++++ 203++++ 204 ++++ 205 +++ 206 ++++ 207 +++ 208 ++++ 209 +++ 210 +++ 211 ++++212 ++++ 213 +++ 214 ++++ 215 +++ 216 ++++ 217 +++ 218 ++++ 219 +++ 220++++ 221 ++++ 222 ++++ 223 ++ 224 ++++ 225 +++ 226 ++++ 227 ++++ 228++++ 229 ++++ 230 ++++ 231 + 232 +++ 233 +++ 234 +++ 235 +++ 236 +++ 237++ 238 ++++ 239 ++++ 240 ++++ 241 ++++ 242 ++++ 243 ++ 244 ++ 245 ++ 246+++ 247 +++ 248 ++++ 249 ++++ 250 +++ 251 +++ 252 +++ 253 ++++ 254 ++++255 +++ 256 ++++ 257 +++ 258 ++++ 259 ++++ 260 + 261 +++ 262 +++ 263++++ 264 ++++ 265 ++++ 266 ++++ 267 ++++ 268 +++ 269 ++++ 270 +++ 271++++ 272 ++++ 273 ++++ 274 +++ 275 ++++ 276 ++++ 277 ++++ 278 + 279 ++++280 ++++ 281 ++++ 282 ++++ 283 ++++ 284 +++ 285 ++++ 303 +++ 304 +++ 305+++ 306 ++ 307 +++ 308 +++ 309 +++ 310 +++ 311 ++++ 313 ++++ 314 ++++316 +++ 317 +++ 318 ++++ 319 ++++ 320 ++++ 321 ++++ 322 +++ 323 ++++ 324++++ 325 + 326 +++ 327 ++++ 328 ++ 329 ++++ 330 ++++ 331 ++++ 332 ++++333 ++ 334 ++ 335 +++ 336 +++ 337 ++++ 338 ++ 339 ++++ 341 ++++ 342 +++343 +++ 344 ++++ 345 ++++ 346 ++++ 347 ++++ 348 ++++ 349 ++++ 350 ++++351 ++++ 352 ++++ 353 ++++ 354 ++ 355 ++++ 356 ++++ 357 ++++ 358 +++ 359+++ 360 +++ 361 ++++ 362 ++++ 363 ++++ 364 ++++ 365 ++++ 366 ++++ 367++++ 368 ++++ 369 ++++ 370 ++++ 371 ++++ 372 ++++ 373 ++++ 374 ++++ 375++++ 376 +++ 377 +++ 378 ++++ 379 ++++ 380 ++++ 382 ++++ 383 ++++ 384+++ 385 +++ 386 +++ 387 ++++ 388 + 389 +++ 390 +++ 391 ++++ 392 ++++ 393++++ 394 ++++ 395 +++ 396 ++++ 397 +++ 398 +++ 399 ++++ 400 ++++ 401++++ 402 +++ 403 +++ 404 +++ 405 ++++ 406 +++ 407 +++ 408 +++ 409 +++410 +++ 411 ++++ 412 ++++ 413 ++++ 414 ++++ 415 ++++ 416 ++++ 417 +++418 ++++ 419 +++ 420 +++ 421 ++++ 422 ++++ 423 +++ 424 ++++ 425 ++ 426++ 427 ++ 428 ++ 429 ++ 430 +++ 431 +++ 432 +++ 433 ++ 434 ++++ 435 +++436 +++ 437 +++ 438 ++ 439 ++++ 440 ++++ 441 ++++ 442 ++++ 443 ++ 444++++ 445 +++ 446 +++ 447 ++++ 448 ++++ 449 ++++ 450 ++++ 451 ++++ 452+++ 453 ++++ 454 +++ 455 +++ 456 +++ 457 +++ 458 ++ 459 + 460 + 461 ++462 + 463 ++ 464 +++ 465 ++ 466 ++ 467 ++ 468 +++ 469 ++ 470 ++ 471 ++473 ++++ 474 ++++ 475 ++++ 476 ++++ 477 ++++ 478 ++++ 481 ++++ 482 +++483 ++++ 484 ++++ 485 ++++ 486 ++++ 487 ++++ 488 +++ 489 ++++ 490 ++++491 ++++ 492 ++++ 493 ++++ 494 +++ 495 ++++ 496 + 497 + 498 + 499 + 500+++ 501 + 502 ++ 503 ++ 504 ++++ 505 ++++ 506 +++ 507 ++++ 508 ++++ 509++++ 510 ++++ 511 +++ 512 ++++ 513 ++++ 514 ++++ 515 ++++ 516 ++++ 517+++ 518 ++++ 519 +++ 520 ++++ 521 ++++ 522 +++ 523 ++++ 524 ++++ 525 +++526 ++++ 527 ++++ 528 +++ 529 ++++ 530 ++++ 531 ++++ 532 ++++ 533 +++534 ++++ 535 +++ 536 ++ 537 ++++ 538 ++++ 539 ++++ 540 ++++ 541 ++++ 542+++ 543 ++++ 544 ++++ 545 ++++ 546 ++++ 547 ++++ 548 ++++ 549 ++++ 550++++ 551 ++++ 552 ++++ 553 ++++ 554 +++ 555 +++ 556 ++++ 557 ++++ 558+++ 559 ++++ 560 +++ 561 ++++ 562 +++ 563 ++++ 564 ++++ 565 ++++ 566++++ 567 ++++ 568 ++++ 569 ++++ 570 ++++ 571 ++++ 572 ++++ 573 ++++ 574++++ 575 ++++ 576 ++++ 577 ++++ 578 ++++ 579 + 580 ++++ 581 ++++ 582++++ 583 ++++ 584 ++++ 585 ++++ 586 ++++ 587 ++++ 588 ++++ 589 ++++ 590++++ 591 ++++ 592 ++++ 593 + 594 ++++ 595 ++++ 596 + 597 + 598 ++++ 599++++ 600 ++ 601 ++++ 602 ++++ 603 ++++ 604 ++++ 605 ++++ 606 +++ 607 +++608 +++ 609 ++++ 610 ++++ 611 +++ 612 ++++ 613 ++++ 614 ++++ 615 +++ 616++++ 617 ++++ 618 ++++ 619 ++++ 620 ++++ 621 ++++ 622 ++++ 623 ++++ 624+++ 625 +++ 626 ++++ 627 ++++ 628 ++++ 629 ++++ 630 ++++ 631 +++ 632++++ 633 ++++ 634 ++++ 635 ++++ 636 ++++ 637 ++++ 638 +++ 639 ++++ 640++++ 641 ++++ 642 +++ 643 ++ 644 ++++ 645 ++++ 646 ++++ 649 ++++ 650++++ 651 ++++ 652 ++++ 653 ++++ 654 ++++ 655 ++ 656 +++ 657 +++ 658 ++659 +++ 660 + 661 ++ 662 ++ 663 +++ 664 ++ 665 ++ 666 ++ 667 ++++ 668++++ 669 ++ 670 ++++ 671 ++++ 672 ++++ 673 ++++ 674 ++ 675 +++ 676 +++677 +++ 678 ++++ 679 ++ 680 ++++ 681 ++++ 682 +++ 683 ++ 684 +++ 685 +++686 +++ 687 +++ 688 ++++ 689 ++++ 690 ++++ 691 ++++ 692 ++++ 693 ++++694 ++++ 695 ++++ 696 ++++ 697 +++ 698 +++ 699 ++++ 700 ++++ 701 + 702+++ 703 ++++ 704 ++++ 705 ++++ 706 +++ 707 + 708 +++ 709 +++ 710 +++ 711+++ 712 ++++ 713 +++ 714 ++++ 715 ++++ 716 ++++ 717 ++++ 718 ++++ 719++++ 720 ++++ 721 ++++ 722 ++++ 723 ++ 724 ++++ 725 ++++ 726 +++ 727++++ 728 +++ 729 ++++ 730 ++++ 731 ++++ 732 ++++ 733 ++ 734 ++++ 735 +++736 ++++ 737 ++++ 738 ++++ 739 +++ 740 +++ 741 +++ 742 ++++ 743 ++++ 744++++ 745 +++ 746 ++++ 747 ++++ 748 ++++ 749 ++++ 750 ++++ 751 ++++ 752++++ 753 ++++ 754 ++++ 756 ++++ 757 +++ 758 ++++ 760 +++ 761 +++ 762++++ 763 ++++ 764 ++++ 765 ++++ 766 +++ 767 +++ 768 ++++ 769 ++++ 770+++ 771 ++ 772 +++ 773 +++ 774 ++++ 775 ++++ 776 +++ 777 +++ 778 ++++779 ++++ 780 ++++ 781 +++ 782 +++ 783 ++++ 784 ++++ 785 ++++ 786 ++++787 ++++ 788 +++ 789 +++ 790 ++++ 791 ++++ 793 +++ 794 ++++ 795 ++++ 796++++ 797 +++ 798 ++++ 799 ++++ 800 ++++ 801 ++++ 802 ++++ 803 +++ 804+++ 805 +++ 806 ++ 807 ++++ 808 ++++ 809 ++++ 810 ++++ 811 ++++ 812 ++++813 ++++ 814 ++++ 815 ++++ 816 ++++ 817 ++++ 818 ++++ 819 + 820 ++++ 821++++ 822 ++ 823 ++++ 824 ++++ 825 ++++ 826 +++ 827 ++++ 828 ++++ 829++++ 830 ++ 831 ++++ 832 ++++ 833 ++++ 834 ++++ 835 ++++ 836 ++++ 837++++ 838 ++++ 839 ++++ 840 ++++ 841 ++++ 842 ++++ 843 ++++ 844 ++++ 845++++ 846 ++++ 1000 ++ 1001 ++ 1002 ++++ 1003 +++ 1004 ++ 1005 +++ 1006+++ 1007 ++ 1008 +++ 1009 ++ 1010 +++ 1011 ++ 1012 ++ 1013 +++ 1014 +++1015 +++ 1016 ++++ 1017 ++++ 1018 ++++ 1200 ++++ 1201 ++++ 1202 ++++1203 ++++ 1204 +++ 1205 +++ 1206 ++++ 1207 +++ 1208 +++ 1209 ++++ 1210++++ 1211 ++++ 1212 ++++ 1213 ++++ 1214 ++++ 1215 ++++ 1216 ++++ 1217++++ 1218 ++++ 1219 ++++ 1220 ++++ 1221 ++++ 1222 ++++ 1223 ++++ 1224 +1226 ++++ 1227 + 1228 ++++ 1229 ++++ 1230 ++++ 1231 ++++ 1232 ++++ 1233++++ 1234 +++ 1235 +++ 1236 ++ 1237 +++ 1238 ++++ 1239 ++++ 1240 ++++1241 +++ 1242 ++ 1243 ++ 1244 ++++ 1245 + 1246 + 1247 ++++ 1248 + 1249++++ 1250 ++++ 1251 ++++ 1252 ++++ 1253 ++++ 1254 +++ 1255 ++++ 2001++++ 2002 ++++ 2003 ++++ 2004 ++++ 2005 ++++ 2006 ++++ 2007 ++++ 2008++++ 2009 ++++ 2010 ++++ 2011 ++++ 2012 ++++ 2013 ++++ 2014 ++++ 2015++++ 2016 ++++ 2017 ++++ 2018 ++++ 2019 ++++ 2020 ++++ 2021 ++++ 2022++++ 2023 ++++ 2024 ++++ 2025 ++++ 2026 ++++ 2027 ++++ 2028 ++++ 2029++++ 2030 ++++ 2031 ++++ 2032 ++++ 2033 ++++ 2034 ++++ 2035 ++++ 2036++++ 2037 ++++ 2038 ++++ 2039 ++++ 2040 ++++ 2041 ++++ 2042 ++++ 2043++++ 2044 ++++ 2045 ++++ 2046 ++++ 2047 ++++ 2048 ++++ 2049 ++++ 2050++++ 2051 ++++ 2052 ++++ 2053 ++++ 2054 ++++ 2055 ++++ 2056 ++++ 2057++++ 2058 ++++ 2059 ++++ 2060 ++++ 2061 ++++ 2062 ++++ 2063 ++++ 2064++++ 2065 ++++ 2066 ++++ 2067 ++++ 2068 ++++ 2069 ++++ 2070 ++++ 2071++++ 2072 ++++ 2073 ++++ 2074 ++++ 2075 ++++ 2076 +++ 2077 + 2078 ++++2079 ++++ 2080 ++++ 2081 ++++ 2082 ++++ 2083 ++++ 2084 ++++ 2085 +++2086 ++++ 2087 ++++ 2088 ++++ 2089 ++++ 2090 +++ 2091 ++++ 2092 ++++2093 ++++ 2094 ++++ 2095 ++++ 2096 +++ 2097 ++++ 2098 ++++ 2099 ++++2100 ++++ 2101 ++++ 2102 ++++ 2103 +++ 2104 ++++ 2105 ++++ 2106 ++++2107 ++++ 2108 ++++ 2109 ++++ 2110 +++ 2111 ++++ 2112 ++++ 2113 ++++2114 ++++ 2115 ++++ 2116 ++++ 2117 ++++ 2118 ++++ 2119 ++++ 2120 ++++2121 ++++ 2122 ++++ 2123 +++ 2124 ++++ 2125 ++++ 2126 ++++ 2127 ++++2128 +++ 2129 ++++ 2130 ++++ 2131 ++++ 2132 ++++ 2133 ++++ 2134 ++++2135 ++++ 2136 ++++ 2137 ++++ 2138 ++++ 2139 ++++ 2140 ++++ 2141 ++++2142 +++ 2143 ++++ 2144 ++++ 2145 ++++ 2146 ++++ 2147 ++++ 2148 ++++2149 ++++ 2150 ++++ 2151 ++++ 2152 ++++ 2153 ++++ 2154 ++++ 2155 +++2156 +++ 2157 ++++ 2158 ++++ 2159 +++ 2160 ++++ 2161 ++++ 2162 ++++ 2163++++ 2164 ++++ 2165 ++++ 2166 ++++ 2167 ++++ 2168 + 2169 ++++ 2170 ++++2171 ++++ 2172 ++ 2173 ++ 2174 ++++ 2175 ++++ 2176 ++++ 2177 ++++ 2178++++ 2179 ++++ 2180 ++++ 2181 ++++ 2182 ++++ 2183 ++++ 2184 ++++ 2185++++ 2186 +++ 2187 +++ 2188 +++ 2189 +++ 2190 ++++ 2191 ++++ 2192 ++++2193 ++++ 2194 ++++ 2195 ++++ 2196 ++++ 2198 ++++ 2199 +++ 2200 ++++2201 ++++ 2202 ++++ 2203 ++++ 2204 ++++ 2205 ++++ 2206 + 2207 ++++ 2208+++ 2209 ++++ 2210 ++++ 2211 ++

Preferably, a compound of the present application (i.e., a compound offormula (I) or a salt thereof) has an IC₅₀ in an IMAP assay against fulllength PKCι at 150 pM ATP of <40 μM. In one embodiment, a compound ofthe present application has an IC₅₀ in an IMAP assay against full lengthPKCι at 150 μM ATP of 40 μM-10 μM. More preferably, a compound of thepresent application has an IC₅₀ in an IMAP assay against full lengthPKCι at 150 M ATP of 10 μM-1 μM. In one embodiment, a compound of thepresent application has an IC₅₀ in an IMAP assay against full lengthPKCι at 150 pM ATP of 1 μM-0.1 μM. More preferably, a compound of thepresent application has an IC₅₀ in an IMAP assay against full lengthPKCι at 150 μM ATP of <0.1 PM.

Preferably, a compound of the present application (i.e., a compound offormula (I) or a salt thereof) has an IC₅₀ in an IMAP assay againstkinase domain PKCι at 25 μM ATP of <40 μM. In one embodiment, a compoundof the present application has an IC₅₀ in an IMAP assay against kinasedomain PKCι at 25 μM ATP of 40 μM-10 μM. More preferably, a compound ofthe present application has an IC₅₀ in an IMAP assay against kinasedomain PKCι at 25 μM ATP of 10 μM-1 μM. In one embodiment, a compound ofthe present application has an IC₅₀ in an IMAP assay against kinasedomain PKCι at 25 pM ATP of 1 μM-0.1 μM. More preferably, a compound ofthe present application has an IC₅₀ in an IMAP assay against kinasedomain PKCι at 25 μM ATP of <0.1 μM.

As those skilled in the art will appreciate, numerous modifications andvariations of the present application are possible in light of the aboveteachings. It is therefore understood that within the scope of theappended claims, the application may be practiced otherwise than asspecifically described herein, and the scope of the application isintended to encompass all such variations.

Each publication referenced herein is incorporated by reference in itsentirety for all purposes.

Additional preferred Embodiments of the present application include:1. A compound of formula (I)

or a salt form thereof, wherein

-   -   G is a group of formula

-   -   X is chosen from H, C₁₋₁₀alkyl optionally substituted by 1-13        R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R¹⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁸, —C(═O)OR²⁸, —C(═O)NR²⁴R²⁸,        —C(═O)C(═O)R²⁸, —NR₂₄R²⁸, —NR₂₄NR₂₄R²⁸, N═NR²⁸, —NR²⁴OR²⁸,        —NR²⁴C(═O)R²⁸, —NR²⁴C(═O)C(═O)R²⁸, —NR²⁴C(═O)OR²⁸,        —NR²⁴C(═O)C(═O)OR²⁸, —NR²⁴C(═O)NR²⁴R²⁸, —NR²⁴C(═O)NR²⁴C(═O)R²⁸,        —NR²⁴C(═O)NR²⁴C(═O)OR²⁸, —NR²⁴C(═O)C(═O)NR²⁴R²⁸, —NR²⁴S(═O)₂R²⁸,        —NR²⁴S(═O)₂NR²⁴R²⁸, —OR, —OC(═O)R²⁸, —OC(═O)NR²⁴R²⁸,        —OC(═O)OR²⁸, —OS(═O)R²⁸, —OS(═O)₂R²⁸, —OS(═O)₂OR²⁸,        —OS(═O)₂NR²⁴R²⁸, —S(═O)_(n)R²⁸, —S(═O)₂NR²⁴R²⁸, and        —S(═O)NR²⁴R²⁸;    -   R⁷, R⁸, R⁹, R¹², R¹³, R¹⁴, R¹⁵, R^(a), R^(b), R^(c), R^(d),        R^(e), R^(f), R^(g), and R^(h) are independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R¹⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R¹⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R¹⁹, C₆₋₁₁aryl optionally substituted by 1-11        R¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³,        —(═O)C(═O)R²⁰, —C(═NR²⁵)R²⁰, —C(═NR²⁵)NR²²R²³, —C(═NOH)NR²²R²³,        —C(═NOR²⁶)R²⁰, —C(═NNR²²R²³)R²⁰, —C(═NNR²⁴C(═O)R²¹)R²⁰,        —C(═NNR²⁴C(═O)OR²¹)R²⁰, —C(═S)NR²²R²³, —NC, —NO₂, —NR²²R²³,        —NR²⁴NR²²R²³, —N═NR²⁴, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰,        —NR²⁴C(═O)C(═O)R²⁰, —NR²⁴C(═O)OR²¹, —NR²⁴C(═O)C(═O)OR²¹,        —NR²⁴C(═O)NR²²R²³, —NR²⁴C(═O)NR²⁴C(═O)R²⁰,        —NR²⁴C(═O)NR²⁴C(═O)OR²⁰, —NR²⁴C(═NR²⁵)NR²²R²³,        —NR²⁴C(═O)C(═O)NR²²R²³, —NR²⁴C(═S)R²⁰, —NR²⁴C(═S)OR²⁰,        —NR²⁴C(═S)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,        —NR²⁴P(═O)R⁷⁸R⁷⁸, —NR²⁴P(═O)(NR²²R²³)(NR²²R²³),        —NR²⁴P(═)(OR²⁰)(OR²⁰), —NR²⁴P(═O)(SR²⁰)(SR²⁰), —OR²⁰, —OCN,        —OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —OC(═NR²⁵)NR²²R²³,        —OS(═O)R²⁰, —OS(═O)₂R²⁰, —OS(═O)₂OR²⁰, —OS(═O)₂NR²²R²³,        —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR²²R²³)(NR²²R²³), OP(═O)(OR²⁰)(OR²⁰),        —OP(═O)(SR²⁰)(SR²⁰), —Si(R²⁴)₃, —SCN, —S(═O)_(n)R²⁰,        —S(═O)₂OR²⁰, —SO₃R²⁷, —S(═O)₂NR²²R²³, —S(═O)NR²²R²³,        —SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR²²R²³)(NR²²R²³), —SP(═O)(OR²⁰)(OR²⁰),        —SP(═O)(SR²⁰)(SR²⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR²²R²³)(NR²²R²³),        —P(═O)(OR²⁰)(OR²⁰), and —P(═O)(SR²⁰)(SR²⁰);    -   or any of R⁷ and R⁸, R¹² and R¹³, R¹⁴ and R¹⁵, R^(a) and R^(b),        R^(a) and R^(c), R^(a) and R^(e), R^(a) and R^(g), R^(b) and        R^(d), R^(b) and R^(f), R^(b) and R^(h), R^(c) and R^(d), R^(c)        and R^(e), R^(c) and R^(g), R^(d) and R^(f), R^(d) and R^(h),        R^(e) and R^(f), R^(e) and R^(g), R^(f) and R^(h), and R^(g) and        R^(h) can, together with the atoms linking them, form a        C₆₋₁₁aryl optionally substituted by 1-11 R¹⁹, C₃₋₁₁cycloalkyl        optionally substituted by 1-21 R¹⁹, 3-15 membered        heterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15        membered heteroaryl optionally substituted by 1-15 R¹⁹;    -   R¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R³⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R³⁹, C₂₋₆alkynyl optionally substituted by        1-9 R³⁹, C₆₋₁₁aryl optionally substituted by 1-11 R³⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R³⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R³⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R³⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R³⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R³⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R³⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R³⁹, halogen, —CN, —C(═O)R³⁰, —C(═O)OR³⁰, —C(═O)NR³²R³³,        —C(═O)C(═O)R³⁰, —C(═NR³⁵)R³⁰, —C(═NR³⁵)NR³²R³³, —C(═NOH)NR³²R³³,        —C(═NOR³⁶)R³⁰, —C(═NNR³²R³³)R³⁰, —C(═NNR³⁴C(═O)R³¹)R³⁰,        —C(═NNR³⁴C(═O)OR³¹)R³⁰, —C(═S)NR³²R³³, —NC, —NO₂, —NR³²R³³,        —NR³⁴NR³²R³³, —N═NR³⁴, ═NR³⁰, ═NOR³⁰, —NR³⁴OR³⁶, —NR³⁴C(═O)R³⁰,        NR³⁴C(═O)C(═O)R³⁰, —NR³⁴C(═O)OR³¹, —NR³⁴C(═O)C(═O)OR³¹,        —NR³⁴C(═O)NR³²R³³, —NR³⁴C(═O)NR³⁴C(═O)R³⁰,        NR³⁴C(═O)NR³⁴C(═O)OR³⁰, NR³⁴C(═NR³⁵)NR³²R³³,        —NR³⁴C(═O)C(═O)NR³²R³³, —NR³⁴C(═S)R³⁰, —NR³⁴C(═S)OR³⁰,        NR³⁴C(═S)NR³²R³³, —NR³⁴S(═O)₂R³¹, —NR³⁴S(═O)₂NR³²R³³,        NR³⁴P(═O)R⁷⁸R⁷⁸, —NR³⁴P(═O)(NR³²R³³)(NR³²R³³),        —NR³⁴P(═)(OR³⁰)(OR³⁰), —NR³⁴P(═O)(SR³⁰)(SR³⁰), —OR³⁰, ═O, —OCN,        —OC(═O)R³⁰, —OC(═O)NR³²R³³, —OC(═O)OR³⁰, —OC(═NR³⁵)NR³²R³³,        —OS(═O)R³⁰, —OS(═O)₂R³⁰, —OS(═O)₂OR³⁰, —OS(═O)₂NR³²R³³,        —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR³²R³³)(NR³²R³³), —OP(═O)(OR³⁰)(OR³⁰),        —OP(═O)(SR³⁰)(SR³⁰), —Si(R³⁴)₃, —SCN, ═S, —S(═O)_(n)R³⁰,        —S(═O)₂OR³⁰, —SO₃R³⁷, —S(═O)₂NR³²R³³, —S(═O)NR³²R³³,        —SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR³²R³³)(NR³²R³³), —SP(═O)(OR³⁰)(OR³⁰),        —SP(═O)(SR³⁰)(SR³⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR³²R³³)(NR³²R³³),        —P(═O)(OR³⁰)(OR³⁰), and —P(═O)(SR³⁰)(SR³⁰);    -   R²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at        each occurrence is independently chosen from H, C₁₋₆alkyl        optionally substituted by 1-13 R⁴⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R⁴⁹, C₂₋₆alkynyl optionally substituted by        1-9 R⁴⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁴⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁴⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁴⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁴⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁴⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁴⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁴⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁴⁹;

R²⁸ at each occurrence is independently chosen from C₁₋₁₀alkyloptionally substituted by 1-13 R⁴⁹, C₂₋₁₀alkenyl optionally substitutedby 1-11 R⁴⁹, C₂₋₆alkynyl optionally substituted by 1-9 R⁴⁹, C₆₋₁₁aryloptionally substituted by 1-11 R⁴⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R⁴⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R⁴⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁴⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R⁴⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R⁴⁹, 5-15membered heteroaryl optionally substituted by 1-15 R⁴⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R⁴⁹;

-   -   R²², R²³, R³² and R³³ at each occurrence is independently chosen        from H, C₁₋₆alkyl optionally substituted by 1-13 R⁵⁹,        C₂₋₆alkenyl optionally substituted by 1-11 R⁵⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R⁵⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R⁵⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R⁵⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁵⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁵⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁵⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁵⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁵⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁵⁹;        -   or any R²² and R²³ and/or R³² and R³³ may form, together            with the nitrogen atom to which they are attached, a 3-15            membered heterocycloalkyl optionally substituted by 1-28 R⁶⁹            or a 5-15 membered heteroaryl optionally substituted by 1-15            R⁶⁹;    -   R³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence is independently chosen        from C₁₋₆alkyl optionally substituted by 1-13 R⁷⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R⁷⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionally substituted by 1-11        R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁷⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁷⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁷⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁷⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁷⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁷⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³,        —C(═O)C(═O)R⁷⁰, —C(═NR⁷⁵)R⁷⁰, −C(═NR⁷⁵)NR⁷²R⁷³, —C(═NOH)NR⁷²R⁷³,        —C(═NOR⁷⁶)R⁷⁰, —C(═NNR⁷²R⁷³)R⁷⁰, —C(═NNR⁷⁴C(═O)R⁷¹)R⁷⁰,        —C(═NNR⁷⁴C(═O)OR⁷¹)R⁷⁰, —C(═S)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³,        —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, ═NR⁷⁰, ═NOR⁷⁰, —NR⁷⁴OR⁷⁶, —NR⁷⁴C(═O)R⁷⁰,        —NR⁷⁴C(═O)C(═O)R⁷⁰, —NR⁷⁴C(═O)OR⁷¹, NR⁷⁴C(═O)C(═O)OR⁷¹,        —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰,        NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰, NR⁷⁴C(═NR⁷⁵)NR⁷²R⁷³,        —NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —NR⁷⁴C(═S)R⁷⁰, —NR⁷⁴C(═S)OR⁷⁰,        NR⁷⁴C(═S)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³,        —NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²NR⁷³)(NR⁷²R⁷³),        —NR⁷⁴P(═O)(OR⁷⁰)(OR⁷⁰), —NR⁷⁴P(═O)(SR⁷⁰)(SR⁷⁰), —OR⁷⁰, ═O, —OCN,        —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰, —OC(═NR⁷⁵)NR⁷²R⁷³,        —OS(═O)R⁷⁰, —OS(═O)₂R⁷⁰, —OS(═O)₂OR⁷⁰, —OS(═O)₂NR⁷²R⁷³,        —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —OP(═O)(OR⁷⁰)(OR⁷⁰),        —OP(═O)(SR⁷⁰)(SR⁷⁰), —Si(R⁷⁴)₃, —SCN, ═S, —S(═O)_(n)R⁷⁰,        —S(═O)₂OR⁷⁰, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,        —SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),        —SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),        —P(═O)(OR⁷⁰)(OR⁷⁰), and —P(═O)(SR⁷⁰)(SR⁷⁰);    -   R⁷⁰, R⁷¹, R⁷⁴, R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R⁸⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁸⁹,        C₂₋₆alkynyl optionally substituted by 1-9 R⁸⁹, C₆₋₁₁aryl        optionally substituted by 1-11 R⁸⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-19 R⁸⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-21 R⁸⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32        R⁸⁹, 3-15 membered heterocycloalkyl optionally substituted by        1-28 R⁸⁹, 4-21 membered heterocycloalkylalkyl optionally        substituted by 1-40 R⁸⁹, 5-15 membered heteroaryl optionally        substituted by 1-15 R⁸⁹, and 6-21 membered heteroarylalkyl        optionally substituted by 1-27 R⁸⁹;    -   R⁷² and R⁷³ at each occurrence is independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R⁹⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R⁹⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R⁹⁹, C₆₋₁₁aryl optionally substituted by 1-11        R⁹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁹⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁹⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁹⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁹⁹;        -   or any R⁷² and R⁷³ may form, together with the nitrogen atom            to which they are attached, a 3-15 membered heterocycloalkyl            optionally substituted by 1-28 R¹⁰⁹ or a 5-15 membered            heteroaryl optionally substituted by 1-15 R¹⁰⁹;    -   R⁷⁸ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R⁸⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R⁸⁹, C₂₋₆alkynyl optionally substituted by        1-9 R⁸⁹, C₆₋₁₁aryl optionally substituted by 1-11 R⁸⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁸⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁸⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁸⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁸⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁸⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁸⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁸⁹;        -   or any two R⁷⁸ attached to the same phosphorus atom can,            together with the phosphorus atom linking them, form a 3-10            membered heterocycloalkyl optionally substituted by 1-6 R⁸⁹;    -   R⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently        chosen from C₁₋₆alkyl optionally substituted by 1-13 R¹¹⁹,        C₂₋₆alkenyl optionally substituted by 1-11 R¹¹⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R¹¹⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R¹¹⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R¹¹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21        R¹¹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹¹⁹,        3-15 membered heterocycloalkyl optionally substituted by 1-28        R¹¹⁹, 4-21 membered heterocycloalkylalkyl optionally substituted        by 1-40 R¹¹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹¹⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹¹⁹, halogen, —CN, —C(═)R¹¹⁰, —C(═O)OR¹¹⁰,        —C(═O)NR¹¹²R¹¹³, —C(═O)C(═O)R¹¹⁰, —C(═NR¹¹⁵)R¹¹⁰,        —C(═NR¹¹⁵)NR¹¹²R¹¹³, —C(═NOH)NR¹¹²R¹¹³, —C(═NOR¹¹⁶)R¹¹⁰,        —C(═NNR¹¹²R¹¹³)R¹¹⁰, —C(═NNR¹¹⁴C(═O)R¹¹¹)R¹¹⁰,        —C(═NNR¹¹⁴C(═O)OR¹¹¹)R¹¹⁰, —C(═S)NR¹¹²R¹¹³, —NC, —NO₂,        —NR¹¹²R¹¹³, —NR¹¹⁴NR¹¹²R¹¹³, —N═NR¹¹⁴, ═NR¹¹⁰, ═NOR¹¹⁰,        —NR¹¹⁴OR¹¹⁶, —NR¹¹⁴C(═O)R¹¹⁰, —NR¹¹⁴C(═O)C(═O)R¹¹⁰,        NR¹¹⁴C(═O)OR¹¹¹, —NR¹¹⁴C(═O)C(═O)OR¹¹¹, —NR¹¹⁴C(═O)NR¹¹²R¹¹³,        —NR¹¹⁴C(═O)NR¹¹⁴C(═O)R¹¹⁰, —NR¹¹⁴C(═O)NR¹¹⁴C(═O)OR¹¹⁰,        NR¹¹⁴C(═NR¹¹⁵)NR¹¹²R¹¹³, —NR¹¹⁴C(═O)C(═O)NR¹¹²R¹³,        NR¹¹⁴C(═S)R¹¹⁰, NR¹¹⁴C(═S)OR¹¹⁰, —NR¹¹⁴C(═S)NR¹¹²R¹¹³,        —NR¹¹⁴S(═O)₂R¹¹¹, —NR¹¹⁴S(═O)₂NR¹¹²R¹¹³, —NR¹¹⁴P(═O)R¹¹⁸R¹⁸,        —NR¹¹⁴P(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³), —NR¹¹⁴P(═O)(OR¹¹⁰)(OR¹¹⁰),        —NR¹¹⁴P(═O)(SR¹¹⁰)(SR¹¹⁰), —OR¹¹⁰, ═O, —OCN, —OC(═O)R¹¹⁰,        —OC(═O)NR¹¹²R¹¹³, —OC(═O)OR¹¹⁰, —OC(═NR¹¹⁵)NR¹¹²R¹¹³,        —OS(═O)R¹¹⁰, —OS(═O)₂R¹¹⁰, —OS(═O)₂OR¹¹⁰, —OS(═O)₂NR¹¹²R¹¹³,        —OP(═O)R¹¹⁸R¹¹⁸, —OP(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³),        —OP(═O)(OR¹¹⁰)(OR¹¹⁰), —OP(═O)(SR¹¹⁰)(SR¹¹⁰), —Si(R¹¹⁴)₃, —SCN,        ═S, —S(═O)_(n)R¹¹⁰, —S(═O)₂OR¹¹⁰, —SO₃R¹¹¹, —S(═O)₂NR¹¹²R¹¹³,        —S(═O)NR¹¹²R¹¹³, —SP(═O)R¹¹⁸R¹¹⁸, —SP(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³),        —SP(═O)(OR¹¹⁰)(OR¹¹⁰), —SP(═O)(SR¹¹⁰)(SR¹¹⁰), —P(═O)R¹¹R¹¹⁸,        —P(═O)(NR¹¹²R¹¹³)(NR¹¹²R¹¹³), —P(═O)(OR¹¹⁰)(OR¹¹⁰), and        —P(═O)(SR¹¹⁰)(SR¹¹⁰);    -   R¹¹⁰, R¹¹¹, R¹¹⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ at each occurrence is        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R¹²⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹²⁹,        C₂₋₆alkynyl optionally substituted by 1-9 R¹²⁹, C₆₋₁₁aryl        optionally substituted by 1-11 R¹²⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-19 R¹²⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-21 R¹²⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by        1-32 R¹²⁹, 3-15 membered heterocycloalkyl optionally substituted        by 1-28 R¹²⁹, 4-21 membered heterocycloalkylalkyl optionally        substituted by 1-40 R¹²⁹, 5-15 membered heteroaryl optionally        substituted by 1-15 R¹²⁹, and 6-21 membered heteroarylalkyl        optionally substituted by 1-27 R¹²⁹;    -   R¹¹² and R¹³ at each occurrence is independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R¹³⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R¹³⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R¹³⁹, C₆₋₁₁aryl optionally substituted by        1-11 R¹³⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹³⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹³⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹³⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹³⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹³⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹³⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R³⁹;        -   or any R¹¹² and R¹¹³ may form, together with the nitrogen            atom to which they are attached, a 3-15 membered            heterocycloalkyl optionally substituted by 1-28 R¹⁴⁹ or a            5-15 membered heteroaryl optionally substituted by 1-15 R⁴⁹;

R¹¹⁸ at each occurrence is independently chosen from C₁₋₆alkyloptionally substituted by 1-13 R¹²⁹, C₂₋₆alkenyl optionally substitutedby 1-11 R¹²⁹, C₂₋₆alkynyl optionally substituted by 1-9 R¹²⁹, C₆₋₁₁aryloptionally substituted by 1-11 R¹²⁹, C₇₋₁₆arylalkyl optionallysubstituted by 1-19 R¹²⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21R¹²⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹²⁹, 3-15membered heterocycloalkyl optionally substituted by 1-28 R¹²⁹, 4-21membered heterocycloalkylalkyl optionally substituted by 1-40 R¹²⁹, 5-15membered heteroaryl optionally substituted by 1-15 R¹²⁹, and 6-21membered heteroarylalkyl optionally substituted by 1-27 R¹²⁹;

-   -   R¹¹⁹, R¹²⁹, R¹³⁹ and R¹⁴⁹ at each occurrence is independently        chosen from C₁₋₆alkyl optionally substituted by 1-13 R¹⁵⁹,        C₂₋₆alkenyl optionally substituted by 1-11 R¹⁵⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R¹⁵⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R¹⁵⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R¹⁵⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21        R¹⁵⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁵⁹,        3-15 membered heterocycloalkyl optionally substituted by 1-28        R¹⁵⁹, 4-21 membered heterocycloalkylalkyl optionally substituted        by 1-40 R¹⁵⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁵⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹⁵⁹, halogen, —CN, —C(═O)R¹⁵⁰, —C(═O)OR¹⁵⁰,        C(═O)NR¹⁵²R¹⁵³, —C(═O)C(═O)R¹⁵⁰, —C(═NR¹⁵⁵)R¹⁵⁰,        —C(═NR¹⁵⁵)NR¹⁵²R¹⁵³, —C(═NOH)NR¹⁵²R¹⁵³, —C(═NOR¹⁵⁶)R¹⁵⁰,        —C(═NNR¹⁵²R¹⁵³)R¹⁵⁰, —C(═NNR¹⁵⁴C(═O)R¹⁵¹)R¹⁵⁰,        —C(═NNR¹⁵⁴C(═O)OR¹⁵¹)R¹⁵⁰, —C(═S)NR¹⁵²R¹⁵³, —NC, —NO₂,        —NR¹⁵²R¹⁵³, —NR¹⁵⁴NR¹⁵²R¹⁵³, —N═NR¹⁵⁴, ═NR¹⁵⁰, ═NOR¹⁵,        —NR¹⁵⁴OR¹⁵⁶, —NR¹⁵⁴C(═O)R¹⁵⁰, —NR¹⁵⁴C(═O)C(═O)R¹⁵⁰,        —NR¹⁵⁴C(═)OR¹⁵¹, —NR¹⁵⁴C(═O)C(═O)OR¹⁵¹, —NR⁵⁴C(═O)NR¹⁵²R¹⁵³,        —NR¹⁵⁴C(═O)NR¹⁵⁴C(═O)R¹⁵⁰, —NR¹⁵⁴C(═O)NR¹⁵⁴C(═O)OR¹⁵⁰,        —NR¹⁵⁴C(═NR¹⁵⁵)NR¹⁵²R¹⁵³, —NR¹⁵⁴C(═O)C(═O)NR¹⁵²R¹⁵³,        —NR¹⁵⁴C(═S)R¹⁵⁰, —NR¹⁵⁴C(═S)OR¹⁵⁰, —NR¹⁵⁴C(═S)NR¹⁵²R¹⁵³,        NR¹⁵⁴S(═O)₂R¹⁵¹, NR¹⁵⁴S(═O)₂NR¹⁵²R¹⁵³, —NR¹⁵⁴P(═O)R¹⁵⁸R¹⁵⁸,        —NR¹⁵⁴P(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³), —NR¹⁵⁴P(═O)(OR¹⁵⁰)(OR¹⁵⁰),        —NR¹⁵⁴P(═O)(SR¹⁵⁰)(SR¹⁵⁰),—OR¹⁵⁰, ═O, —OCN, —OC(═O)R¹⁵⁰,        —OC(═O)NR¹⁵²R¹⁵³, —OC(═O)OR¹⁵⁰, OC(═NR¹⁵⁵)NR¹⁵²R¹⁵³,        —OS(═O)R¹⁵⁰, —OS(═O)₂R¹⁵⁰, —OS(═O)₂OR¹⁵⁰, —OS(═O)₂NR¹⁵²R¹⁵³,        —OP(═O)R¹⁵⁸R¹⁵⁸, —OP(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³),        —OP(═O)(OR¹⁵⁰)(OR¹⁵⁰),—OP(═O)(SR(SR¹⁵⁰)(SR¹⁵⁰), —Si(R¹⁵⁴)₃,        —SCN, ═S, —S(═O)_(n)R¹⁵⁰, —S(═O)₂OR¹⁵⁰, —SO₃R¹⁵¹⁵,        —S(═O)₂NR¹⁵²R¹⁵³, —S(═O)NR¹⁵²R¹⁵³, —SP(═O)R¹⁵⁸R¹⁵⁸,        —SP(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³), —SP(═O)(OR¹⁵⁰)(OR¹⁵⁰),        —SP(═O)(SR¹⁵⁰)(SR¹⁵⁰), —P(═O)R¹⁵⁸R¹⁵⁸,        —P(═O)(NR¹⁵²R¹⁵³)(NR¹⁵²R¹⁵³), —P(═O)(OR¹⁵⁰)(OR¹⁵⁰), and        —P(═O)(SR¹⁵⁰)(SR¹⁵⁰);

R⁵¹⁰, R¹⁵¹, R¹⁵⁴, R¹⁵⁵, R¹⁵⁶ and R¹⁵⁷ at each occurrence isindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-13R¹⁶⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁶⁹, C₂₋₆alkynyloptionally substituted by 1-9 R¹⁶⁹, C₆₋₁₁aryl optionally substituted by1-11 R¹⁶⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁶⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁶⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁶⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁶⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R¹⁶⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁶⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R⁶⁹;

-   -   R¹⁵² and R¹⁵³ at each occurrence is independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R¹⁷⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R¹⁷⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R¹⁷⁹, C₆₋₁₁aryl optionally substituted by        1-11 R¹⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁷⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁷⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁷⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁷⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹⁷⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁷⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R¹⁷⁹;        -   or any R¹⁵² and R¹⁵³ may form, together with the nitrogen            atom to which they are attached, a 3-15 membered            heterocycloalkyl optionally substituted by 1-28 R¹⁸⁹ or a            5-15 membered heteroaryl optionally substituted by 1-15            R¹⁸⁹;    -   R¹⁵⁸ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R¹⁶⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R¹⁶⁹, C₂₋₆alkynyl optionally substituted by        1-9 R¹⁶⁹, C₆₋₁₁aryl optionally substituted by 1-11 R¹⁶⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R¹⁶⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁶⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁶⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R¹⁶⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R¹⁶⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁶⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R⁶⁹;    -   R¹⁵⁹, R¹⁶⁹, R¹⁷⁹ and R¹⁸⁹ at each occurrence is independently        chosen from C₁₋₆alkyl optionally substituted by 1-13 R¹⁹⁹,        C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹⁹, C₂₋₆alkynyl        optionally substituted by 1-9 R¹⁹⁹, C₆₋₁₁aryl optionally        substituted by 1-11 R¹⁹⁹, C₇₋₁₆arylalkyl optionally substituted        by 1-19 R¹⁹⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21        R¹⁹⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R¹⁹⁹,        3-15 membered heterocycloalkyl optionally substituted by 1-28        R¹⁹⁹, 4-21 membered heterocycloalkylalkyl optionally substituted        by 1-40 R¹⁹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R¹⁹⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R¹⁹⁹, halogen, —CN, —C(═O)R¹⁹⁰, —C(═O)OR¹⁹⁰,        —C(═O)NR¹⁹²R¹⁹³, —C(═O)C(═O)R¹⁹⁰, —C(═NR¹⁹⁵)R¹⁹⁰,        —C(═NR¹⁹⁵)NR¹⁹²R¹⁹³, —C(═NOH)NR¹⁹²R¹⁹³, —C(═NOR¹⁹⁶)R¹⁹⁰,        —C(═NNR¹⁹²R¹⁹³)R¹⁹⁰, —C(═NNR¹⁹⁴C(═O)R¹⁹¹)R¹⁹⁰,        —C(═NNR¹⁹⁴C(═O)OR¹⁹¹)R¹⁹⁰, —C(═S)NR¹⁹²R¹⁹³, —NC, —NO₂,        —NR¹⁹²R¹⁹³, —NR¹⁹⁴NR¹⁹²R¹⁹³, —N═NR¹⁹⁴, ═NR¹⁹⁰, ═NOR¹⁹⁰,        —NR¹⁹⁴OR¹⁹⁶, —NR¹⁹⁴C(═O)R¹⁹⁰, —NR¹⁹⁴C(═O)C(═O)R¹⁹⁰,        —NR¹⁹⁴C(═O)OR¹⁹¹, —NR¹⁹⁴C(═O)C(═)OR¹⁹¹, —NR¹⁹⁴C(═O)NR¹⁹²R¹⁹³,        —NR¹⁹⁴C(═O)NR¹⁹⁴C(═O)R¹⁹⁰, —NR¹⁹⁴C(═O)NR¹⁹⁴C(═O)OR¹⁹⁰,        NR¹⁹⁴C(═NR¹⁹⁵)NR¹⁹²R¹⁹³, —NR¹⁹⁴C(═O)C(═O)NR¹⁹²R¹⁹³,        NR¹⁹⁴C(═S)R¹⁹⁰, —NR¹⁹⁴C(═S)OR¹⁹⁰, —NR¹⁹⁴C(═S)NR¹⁹²R¹⁹³,        NR¹⁹⁴S(═O)₂R¹⁹¹, —NR¹⁹⁴S(═O)₂NR¹⁹²R¹⁹³, —NR¹⁹⁴C(═O)R¹⁹⁸R¹⁹⁸,        —NR¹⁹⁴P(═O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³), —NR¹⁹⁴P(═O)(OR¹⁹⁰)(OR¹⁹⁰),        —NR¹⁹⁴P(═O)(SR¹⁹⁰)(SR¹⁹⁰),—OR¹⁹⁰, ═O, —OCN, —OC(═O)R¹⁹⁰,        —OC(═O)NR¹⁹²R¹⁹³, —OC(═O)OR¹⁹⁰, —OC(═NR¹⁹⁵)NR¹⁹²R¹⁹³,        —OS(═O)R¹⁹⁰, —OS(═O)₂R¹⁹⁰, —OS(═O)₂OR¹⁹⁰, —OS(═O)₂NR¹⁹²R¹⁹³,        —OP(═O)R¹⁹⁸R¹⁹⁸, —OP(═O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³),        —OP(═O)₂(OR¹⁹⁰)(OR¹⁹⁰), —OP(═O)(SR¹⁹⁰)(SR¹⁹⁰), —Si(R¹⁹⁴)₃, —SCN,        ═S, —S(═O)_(n)R¹⁹⁰, —S(═O)₂R¹⁹⁰, —SO₃R¹⁹¹⁹, —S(═O)₂NR¹⁹²R¹⁹³,        —S(═O)NR¹⁹²R¹⁹³, —SP(═O)R¹⁹⁸R¹⁹⁸, —SP(═O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³),        —SP(═O)(OR¹⁹⁰)(OR¹⁹⁰), —SP(═O)(SR¹⁹⁰)(SR¹⁹⁰), —P(═O)R¹⁹⁸R¹⁹⁸,        —P(═O)(NR¹⁹²R¹⁹³)(NR¹⁹²R¹⁹³), —P(═O)(OR¹⁹⁰)(OR¹⁹⁰), and        —P(═O)(SR¹⁹⁰)(SR¹⁹⁰);    -   R¹⁹⁰, R¹⁹¹, R¹⁹⁴, R¹⁹⁵, R¹⁹⁶ and R¹⁹⁷ at each occurrence is        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R²⁰⁹, C₂₋₆alkenyl optionally substituted by 1-11 R²⁰⁹,        C₂₋₆alkynyl optionally substituted by 1-9 R²⁰⁹, C₆₋₁₁aryl        optionally substituted by 1-11 R²⁰⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-19 R²⁰⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-21 R²⁰⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by        1-32 R²⁰⁹, 3-15 membered heterocycloalkyl optionally substituted        by 1-28 R²⁰⁹, 4-21 membered heterocycloalkylalkyl optionally        substituted by 1-40 R²⁰⁹, 5-15 membered heteroaryl optionally        substituted by 1-15 R²⁰⁹, and 6-21 membered heteroarylalkyl        optionally substituted by 1-27 R²⁰⁹;    -   R¹⁹² and R¹⁹³ at each occurrence is independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R²¹⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R²¹⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R²¹⁹, C₆₋₁₁aryl optionally substituted by        1-11 R²¹⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R²¹⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R²¹⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R²¹⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R²¹⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R²¹⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R²¹⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R²¹⁹;        -   or any R¹⁹² and R¹⁹³ may form, together with the nitrogen            atom to which they are attached, a 3-15 membered            heterocycloalkyl optionally substituted by 1-28 R²²⁹ or a            5-15 membered heteroaryl optionally substituted by 1-15            R²²⁹;    -   R¹⁹⁸ at each occurrence is independently chosen from C₁₋₆alkyl        optionally substituted by 1-13 R²⁰⁹, C₂₋₆alkenyl optionally        substituted by 1-11 R²⁰⁹, C₂₋₆alkynyl optionally substituted by        1-9 R²⁰⁹, C₆₋₁₁aryl optionally substituted by 1-11 R²⁰⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-19 R²⁰⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R²⁰⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R²⁰⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R²⁰⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R²⁰⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R²⁰⁹, and 6-21 membered heteroarylalkyl optionally        substituted by 1-27 R²⁰⁹;    -   R¹⁹⁹, R²⁰⁹, R²¹⁹ and R²²⁹ at each occurrence is independently        chosen from C₁₋₆alkyl optionally substituted by 1-13 halogen,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₁aryl, C₇₋₁₆arylalkyl,        C₃₋₁₁cycloalkyl, C₄₋₁₇cycloalkylalkyl, 3-15 membered        heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15        membered heteroaryl, 6-21 membered heteroarylalkyl, halogen,        —CN, —C(═O)R²³⁰, —C(═)OR²³⁰, —C(═O)NR²³⁰R²³⁰, —C(═O)C(═O)R²³⁰,        —C(═NR²³⁰)R²³⁰, —C(═NR²³⁰)NR²³⁰R²³⁰, —C(═NOH)NR²³⁰R²³⁰,        —C(═NOR²³⁰)R²³⁰, —C(═NNR²³R²³⁰)R²³⁰, —C(═NNR²³⁰C(═O)R²³⁰)R²³⁰,        —C(═NNR²³⁰C(═O)OR²³⁰)R²³⁰, —C(═S)NR²³⁰R²³⁰, —NC, —NO₂,        —NR²³⁰R²³⁰, NR²³⁰NR²³⁰R²³⁰, —N═NR²³⁰, ═NR²³⁰, ═NOR²³⁰,        —NR²³⁰OR²³⁰, —NR²³⁰C(═O)R²³⁰, NR³⁰C(═O)C(═O)R²³⁰,        —NR²³⁰C.(═O)OR²³⁰, —NR³⁰C(═O)C(═O)OR²³⁰, —NR²³⁰C(═O)NR²³⁰R²³⁰,        —NR²³⁰C(═O)NR²³⁰C(═O)R²³⁰C(═O)R²³⁰, —NR²³⁰C(═O)NR²³⁰C(═O)OR²³⁰,        —NR²³⁰C(═NR²³⁰)NR²³⁰R²³⁰, —NR²³⁰C(═O)C(═O)NR²³⁰R²³⁰,        —NR²³⁰C(═S)R²³⁰, —NR²³⁰C(═S)OR²³⁰, —NR²³⁰C(═S)NR²³⁰R²³⁰,        —NR²³⁰S(═O)₂R²³⁰, —NR²³⁰S(═O)₂NR²³⁰R²³⁰, —NR²³⁰P(═O)R²³¹R²³¹,        —NR²³⁰P(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰), —NR²³⁰P(═O)(OR²³⁰)(OR²³⁰),        —NR²³⁰P(═O)(SR²³⁰)(SR²³⁰), —OR²³⁰, ═O, —OCN, —OC(═O)R²³⁰,        —OC(═O)NR²³⁰R²³⁰, —OC(═O)OR²³⁰, —OC(═NR²³⁰)NR²³⁰R²³⁰,        —OS(═O)R²³⁰, —OS(═O)₂R²³⁰, —OS(═O)₂OR²³⁰, —OS(═O)₂NR²³⁰R²³⁰,        —OP(═O)R²³¹R²³¹, —OP(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰),        —OP(═O)(OR²³⁰)(OR²³⁰), —OP(═O)(SR²³⁰)(SR²³⁰), —Si(R²³⁰)₃, —SCN,        ═S, —S(═O)_(n)R²³⁰, —S(═O)₂OR²³⁰, —SO₃R²³⁰, —S(═O)₂NR²³⁰R²³⁰,        —S(═O)NR²³⁰R²³⁰, —SP(═O)R²³¹R²³¹, —SP(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰),        —SP(═O)(OR²³⁰)(OR²³⁰), —SP(═O)(SR²³⁰)(SR²³⁰), —P(═O)R²³¹R²³¹,        —P(═O)(NR²³⁰R²³⁰)(NR²³⁰R²³⁰), —P(═O)(OR²³⁰)(OR²³⁰), and        —P(═O)(SR²³⁰)(SR²³⁰);    -   R²³⁰ at each occurrence is independently chosen from H,        C₁₋₆alkyl and C₁₋₆-haloalkyl;    -   R²³¹ at each occurrence is independently chosen from C₁₋₆alkyl        and C₁₋₆-haloalkyl; and    -   n at each occurrence is independently chosen from 0, 1, and 2;        with the proviso that the compound is not

-   -   in which D is H or

-   -   or a salt form thereof;

in which D is

or a salt form thereof; or

-   -   in which D is H or —CH₃, or a salt form thereof.        2. A compound as defined in preferred Embodiment 1, wherein X is        chosen from 3-10 membered heterocycloalkyl optionally        substituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionally        substituted by 1-6 R¹⁹, —C(═O)R²⁸, —C(═O)NR²⁴R²⁸, —NR²⁴R²⁸,        —NR²⁴C(═O)R²⁸, —NR²⁴S(═O)₂R²⁸, and —OR²⁸.        3. A compound as defined in preferred Embodiment 1, wherein X is        chosen from 5-6 membered heterocycloalkyl optionally substituted        by 1-6 R¹⁹, and —NR²⁴R²⁸.        4. A compound as defined in preferred Embodiment 1, wherein X is        chosen from morpholinyl optionally substituted by 1-6 R¹⁹,        piperidinyl optionally substituted by 1-6 R¹⁹, piperazinyl        optionally substituted by 1-6 R¹⁹, and —NR²⁴R²⁸.        5. A compound as defined in preferred Embodiment 1, wherein X is

and

-   -   A is —NR¹R², —CR^(i)R^(j)R^(k), —OR^(18a), or —SR¹⁸b;    -   Q is —NR¹¹—, —CR^(m)R^(n)—, —O—, or —S—;    -   R^(k) is H, halogen, —CN, —NO₂, —NR¹⁶R¹⁷, —OR^(18c), —SR^(18d),        or —CR^(o)R^(p)R^(q);    -   R^(q) is H, halogen, —CN, —NO₂, —NR^(16a)R^(17a) or —OR^(18e);    -   R¹, R², R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b),        R^(18c), R^(18d), and R^(18e) are independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-13 R⁷⁹, C₂₋₆alkenyl        optionally substituted by 1-11 R⁷⁹, C₂₋₆alkynyl optionally        substituted by 1-9 R⁷⁹, C₆₋₁₁aryl optionally substituted by 1-11        R⁷⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19 R⁷⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁷⁹,        C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁷⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁷⁹,        4-21 membered heterocycloalkylalkyl optionally substituted by        1-40 R⁷⁹, 5-15 membered heteroaryl optionally substituted by        1-15 R⁷⁹, 6-21 membered heteroarylalkyl optionally substituted        by 1-27 R⁷⁹, and —OR⁷⁰;    -   R³, R⁴, R⁵, R⁶, R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are        independently chosen from H, C₁₋₆alkyl optionally substituted by        1-13 R⁷⁹, C₂₋₆alkenyl optionally substituted by 1-11 R⁷⁹,        C₂₋₆alkynyl optionally substituted by 1-9 R⁷⁹, C₆₋₁₁aryl        optionally substituted by 1-11 R⁷⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-19 R⁷⁹, C₃₋₁₁cycloalkyl optionally substituted        by 1-21 R⁷⁹, C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32        R⁷⁹, 3-15 membered heterocycloalkyl optionally substituted by        1-28 R⁷⁹, 4-21 membered heterocycloalkylalkyl optionally        substituted by 1-40 R⁷⁹, 5-15 membered heteroaryl optionally        substituted by 1-15 R⁷⁹, 6-21 membered heteroarylalkyl        optionally substituted by 1-27 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰,        —C(═)OR⁷⁰, —C(═O)NR⁷²R⁷³, —C(═O)C(═O)R⁷⁰, —C(═NR⁷⁵)R⁷⁰,        —C(═NR⁷⁵)NR⁷²R⁷³, —C(═NOH)NR⁷²R⁷³, —C(═NOR⁷⁶)R⁷⁰,        —C(═NNR⁷²R⁷³)R⁷⁰, —C(═NNR⁷⁴C(═O)R⁷)R⁷¹)R⁷⁰,        —C(═NNR⁷⁴C(═O)OR⁷¹)R⁷⁰, —C(═S)NR⁷²R⁷³, —NC, —NO₂, —NR⁷²R⁷³,        —NR⁷⁴NR⁷²R⁷³, —N═NR⁷⁴, —NR⁷⁴OR⁷⁶, NR⁷⁴C(═O)R⁷⁰,        —NR⁷⁴C(═O)C(═O)R⁷⁰, NR⁷⁴C(═O)OR⁷¹, —NR⁷⁴C(═O)C(═)OR⁷¹,        —NR⁷⁴C(═O)NR⁷²R⁷³, —NR⁷⁴C(═O)NR⁷⁴C(═O)R⁷⁰,        —NR⁷⁴C(═O)NR⁷⁴C(═O)OR⁷⁰, —NR⁷⁴C(═NR⁷⁵)NR⁷²R⁷³,        —NR⁷⁴C(═O)C(═O)NR⁷²R⁷³, —NR⁷⁴C(═S)R⁷⁰, NR⁷⁴C(═S)OR⁷⁰,        —NR⁷⁴C(═S)NR⁷²R⁷³, —NR⁷⁴S(═O)₂R⁷¹, —NR⁷⁴S(═O)₂NR⁷²R⁷³,        —NR⁷⁴P(═O)R⁷⁸R⁷⁸, —NR⁷⁴P(═O)(NR⁷²R⁷³)(NR⁷²R⁷³),        —NR⁷⁴P(═O)(OR⁷⁰)(OR⁷⁰), —NR⁷⁴P(═O)(SR⁷⁰)(SR⁷⁰), —OR⁷⁰, —OCN,        —OC(═O)R⁷⁰, —OC(═O)NR⁷²R⁷³, —OC(═O)OR⁷⁰, —OC(═NR⁷⁵)NR⁷²R⁷³,        —OS(═O)R⁷⁰, —OS(═O)₂R⁷⁰, —OS(═O)₂OR⁷⁰, —OS(═O)₂NR⁷²R⁷³,        —OP(═O)R⁷⁸R⁷⁸, —OP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —OP(═O)(OR⁷⁰)(OR⁷⁰),        —OP(═O)(SR⁷⁰)(SR⁷⁰), —Si(R⁷⁴)₃, —SCN, —S(═O)_(n)R⁷⁰,        —S(═O)₂OR⁷⁰, —SO₃R⁷⁷, —S(═O)₂NR⁷²R⁷³, —S(═O)NR⁷²R⁷³,        —SP(═O)R⁷⁸R⁷⁸, —SP(═O)(NR⁷²R⁷³)(NR⁷²R⁷³), —SP(═O)(OR⁷⁰)(OR⁷⁰),        —SP(═O)(SR⁷⁰)(SR⁷⁰), —P(═O)R⁷⁸R⁷⁸, —P(═O)R⁷³R⁷³)(NR⁷²R⁷³),        —P(═O)(OR⁷⁰)(OR⁷⁰), and —P(═O)(SR⁷⁰)(SR⁷⁰);    -   or any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and        R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶        and R³, R¹⁶ and R, R¹⁶ and R¹¹, R¹⁶ and R^(n), R^(j) and R¹¹,        R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹, R^(18a) and        R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹, R^(18b)        and R^(n), R^(18c) and R^(i), R^(18c) and R³, R^(18c) and R⁵,        R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i), R^(18d)        and R³, R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and R^(n)        can, together with the atoms linking them, form a 3-15 membered        heterocycloalkyl optionally substituted by 1-28 R⁷⁹ or a 5-15        membered heteroaryl optionally substituted by 1-15 R⁷⁹;    -   or any of R³ and R⁴, R³ and R⁶, R⁵ and R⁶, R^(i) and R^(j),        R^(i) and R⁴, R^(i) and R⁵, R^(i) and R^(n), R^(m) and R^(n), R⁴        and R^(m), and R⁶ and R^(m) can, together with the atoms linking        them, form a C₆₋₁₁aryl optionally substituted by 1-11 R⁷⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁷⁹, 3-15        membered heterocycloalkyl optionally substituted by 1-28 R⁷⁹ or        a 5-15 membered heteroaryl optionally substituted by 1-15 R⁷⁹;    -   or R⁴ and R⁵ or R^(n) and R⁵ can together form a double bond;    -   or any of R³ and R⁴, R⁵ and R⁶, R^(i) and R^(j), and R^(m) and        R^(n) can together form ═O, ═NR⁷⁰, ═NOR⁷⁰, or ═S.        6. A compound as defined in preferred Embodiment 5, wherein R¹,        R², R¹¹, R¹⁶, R¹⁷, R^(16a) R^(17a), R^(18a), R^(18b), R^(18c),        R^(18d), and Rise are independently chosen from H, C₁₋₆alkyl        optionally substituted by 1-6 R⁷⁹, and C₇₋₁₆arylalkyl optionally        substituted by 1-6 R⁷⁹; R³, R⁴, R⁵, R⁶, R^(i), R^(j), R^(m),        R^(n), R^(o), and R^(p) are independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyl        optionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted        by 1-6 R⁷⁹, —CN, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, and —OR⁷⁰;        or any of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹ and        R^(n), R⁴ and R¹, R¹⁶ and R⁵, R^(j) and R¹¹, and R^(18a) and R¹¹        can, together with the atoms linking them, form a 3-11 membered        heterocycloalkyl optionally substituted by 1-6 R⁷⁹; or R³ and R⁴        can together form ═O.        7. A compound as defined in preferred Embodiment 5, wherein R¹,        R, R¹⁶, R¹⁷, R^(16a), R^(17a) R^(18a), R^(18b), R^(18c),        R^(18d), and R^(18e) are independently chosen from H and        C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹; R² is chosen from        H, C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, and        C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹; R⁴, R⁵, R⁶,        R^(i), R^(j), R^(m), R^(n), R^(o), and R^(p) are independently        chosen from H and C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹;        R³ is chosen from H, C₁₋₆alkyl optionally substituted by 1-6        R⁷⁹, C₂₋₆alkynyl optionally substituted by 1-6 R⁷⁹,        C₇₋₁₆arylalkyl optionally substituted by 1-6 R⁷⁹,        C₃₋₁₀cycloalkyl optionally substituted by 1-6 R⁷⁹, 3-10 membered        heterocycloalkyl optionally substituted by 1-6 R⁷⁹, halogen,        —CN, —C(═O)R⁷⁰, —C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³, —NO₂, —NR⁷²R⁷³,        —NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰, —S(═O)_(n)R⁷⁰,        and —S(═O)₂NR⁷²R⁷³; or any of R¹ and R², R¹ and R³, R¹ and R⁵,        R¹ and R, R¹ and R¹¹, R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶        and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ and R^(n),        R^(j) and R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹,        R^(18a) and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and        R¹¹, R^(18b) and R^(n), R^(18c) and R^(i), R^(18c) and R³,        R^(18c) and R⁵, R^(18c) and R¹¹, R^(18c) and R^(n), R^(18d) and        R^(i), R^(18d) and R³, R^(18d) and R⁵, R^(18d) and R¹¹, and        R^(18d) and R^(n) can, together with the atoms linking them,        form a 3-11 membered heterocycloalkyl optionally substituted by        1-6 R⁷⁹; or any of R³ and R⁴, R³ and R⁶, R⁵ and R⁶, R^(i) and        R^(j), R^(i) and R⁴, R^(i) and R⁵, R^(i) and R^(n), R^(m) and        R^(n), R⁴ and R^(m), and R⁶ and R^(m) can, together with the        atoms linking them, form a C₃₋₁₀cycloalkyl optionally        substituted by 1-6 R⁷⁹, or a 3-11 membered heterocycloalkyl        optionally substituted by 1-6 R⁷⁹; or any of R³ and R⁴, R⁵ and        R⁶, R^(i) and R^(j), and R^(m) and R^(n) can together form ═O.        8. A compound as defined in preferred Embodiments 6 or 7,        wherein 1-2 of R¹ and R², R¹ and R³, R¹ and R⁵, R¹ and R¹¹, R¹        and R^(n), R⁴ and R¹¹, R⁶ and R¹¹, R¹⁶ and R¹⁷, R¹⁶ and R^(i),        R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹, R¹⁶ and R^(n), R^(j) and        R¹¹, R^(18a) and R³, R^(18a) and R⁵, R^(18a) and R¹¹, R^(18a)        and R^(n), R^(18b) and R³, R^(18b) and R⁵, R^(18b) and R¹¹,        R^(18b) and R^(n), R^(18e) and R^(i), R^(18e) and R³, R^(18e)        and R⁵, R¹⁸C and R¹¹, R^(18c) and R^(n), R^(18d) and R^(i),        R^(18d) and R³, R^(18d) and R⁵, R^(18d) and R¹¹, and R^(18d) and        R^(n), together with the atoms linking them, form an optionally        substituted heterocycloalkyl.        9. A compound as defined in preferred Embodiment 5, wherein R¹,        R¹¹, R¹⁶, R¹⁷, R^(16a), R^(17a), R^(18a), R^(18b), R^(18c),        R^(18d), and R^(18e) are H; R² is chosen from H and C₁₋₆alkyl        optionally substituted by 1-6 R⁷⁹; R⁴, R⁵, R⁶, R^(i), R^(j),        R^(m), R^(n), R^(o), and R^(p) are H; R³ is chosen from H,        C₁₋₆alkyl optionally substituted by 1-6 R⁷⁹, C₂₋₆alkynyl        optionally substituted by 1-6 R⁷⁹, C₇₋₁₆arylalkyl optionally        substituted by 1-6 R⁷⁹, C₃₋₁₀cycloalkyl optionally substituted        by 1-6 R⁷⁹, 3-6 membered heterocycloalkyl optionally substituted        by 1-3 R⁷⁹, halogen, —CN, —C(═O)R⁷⁰, C(═O)OR⁷⁰, —C(═O)NR⁷²R⁷³,        —NR⁷²R⁷³, —NR⁷⁴C(═O)R⁷⁰, —NR⁷⁴S(═O)₂R⁷¹, —OR⁷⁰, —OC(═O)R⁷⁰,        —S(═)_(n)R⁷⁰, and —S(═O)₂NR⁷²R⁷³; or any of R¹ and R², R¹ and        R³, R¹ and R⁵, R¹ and R¹¹, R¹ and R^(n), R⁴ and R¹¹, R⁶ and R¹¹,        R¹⁶ and R¹⁷, R¹⁶ and R^(i), R¹⁶ and R³, R¹⁶ and R⁵, R¹⁶ and R¹¹,        R¹⁶ and R^(n), R^(j) and R¹¹, and R^(18a) and R¹¹ can, together        with the atoms linking them, form a 3-11 membered        heterocycloalkyl optionally substituted by 1-6 R⁷⁹; or any of R³        and R⁴, R⁵ and R⁶, R^(i) and R^(j), and R^(m) and R^(n) can        together form ═O.        10. A compound as defined in any of preferred Embodiments 5-9,        wherein R^(q) is —NR^(16a)R^(17a) or —OR^(18e).        11. A compound as defined in any of preferred Embodiments 5-10,        wherein R^(k) is —NR¹⁶R¹⁷ or —OR^(18c).        12. A compound as defined in any of preferred Embodiments 5-11,        wherein A is —NR¹R², —CR^(i)R^(j)R^(k), or —OR^(18a).        13. A compound as defined in any of preferred Embodiments 5-11,        wherein A is —NR¹R²        14. A compound as defined in any of preferred Embodiments 5-13,        wherein Q is —NR¹¹—, —CR^(m)R^(n)—, or —O—.        15. A compound as defined in any of preferred Embodiments 5-13,        wherein Q is —NR¹¹—.        16. A compound as defined in any of preferred Embodiments 1-15,        wherein R⁷, R⁸, and R⁹ are independently chosen from H,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₀aryl, C₇₋₁₁arylalkyl,        C₃₋₇cycloalkyl, C₄₋₈cycloalkylalkyl, 3-7 membered        heterocycloalkyl, 4-8 membered heterocycloalkylalkyl, 5-6        membered heteroaryl, 6-21 membered heteroarylalkyl, halogen,        —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,        —NR²⁴C(═O)R²⁰,—NR²⁴S(═O)₂R²¹, —OR²⁰, —S(═O)_(n)R²⁰, and        —S(═O)₂NR²²R²³; or R⁷ and R⁸ can, together with the atoms        linking them, form a C₆₋₁₀aryl, C₃₋₇cycloalkyl, 3-7 membered        heterocycloalkyl or a 5-6 membered heteroaryl.        17. A compound as defined in any of preferred Embodiments 1-15,        wherein R⁷, R⁸, and R⁹ are independently chosen from H,        C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl        optionally substituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally        substituted by 1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-6        R¹⁹, C₃₋₁₀cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10        membered heterocycloalkyl optionally substituted by 1-6 R¹⁹,        5-10 membered heteroaryl optionally substituted by 1-6 R¹⁹,        halogen, —NR²²R²³, —OR²⁰, and —S(═O)_(n)R²⁰.        18. A compound as defined in any of preferred Embodiments 1-15,        wherein R⁷ is chosen from H, C₁₋₆alkyl optionally substituted by        1-6 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-6 R¹⁹,        C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹, C₃₋₁₀cycloalkyl        optionally substituted by 1-6 R¹⁹, 3-10 membered        heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10        membered heteroaryl optionally substituted by 1-6 R¹⁹, halogen,        —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,        NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰,        —OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; R⁸ is chosen from        H, C₁₋₆alkyl optionally substituted by 1-6 R¹⁹, halogen,        —NR²²R²³, and —OR²⁰; and R⁹ is chosen from H, C₁₋₆alkyl        optionally substituted by 1-6 R¹⁹, C₂₋₆alkenyl optionally        substituted by 1-6 R¹⁹, C₂₋₆alkynyl optionally substituted by        1-6 R¹⁹, C₆₋₁₀aryl optionally substituted by 1-6 R¹⁹,        C₃₋₁₁cycloalkyl optionally substituted by 1-6 R¹⁹, 3-10 membered        heterocycloalkyl optionally substituted by 1-6 R¹⁹, 5-10        membered heteroaryl optionally substituted by 1-6 R¹⁹, halogen,        —CN, —C(═O)R²⁰, —(═O)²⁰, —C(═O)NR²²R²³, —NC, —NO₂, —NR²²R²³,        —NR²⁴C(═O)R²⁰, NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹,        —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —OC(═O)NR²²R²³,        —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.        19. A compound as defined in any of preferred Embodiments 1-15,        wherein R⁷ is chosen from H, C₁₋₆alkyl optionally substituted by        1-3 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-3 R¹⁹,        C₃₋₆cycloalkyl optionally substituted by 1-3 R¹⁹, halogen,        —NR²²R²³, and —OR²⁰; R⁸ is chosen from H and halogen; and R⁹ is        chosen from H, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹,        C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, 3-6 membered        heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-9 membered        heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —NR²²R²³,        —OR²⁰, and —S(═O)_(n)R²⁰.        20. A compound as defined in any of preferred Embodiments 1-19,        wherein R⁸ is H.        21. A compound as defined in any of preferred Embodiments 1-20,        wherein G is a group of formula

and R¹², R¹, R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3 R¹⁹, 3-7 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴S(═O)₂R²¹, —OR²⁰,—S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or either or both of R¹² and R¹³,and/or R¹⁴ and R¹⁵, can, together with the atoms linking them, form aphenyl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionallysubstituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyl optionallysubstituted by 1-3 R¹⁹ or a 5-6 membered heteroaryl optionallysubstituted by 1-3 R¹⁹.22. A compound as defined in any of preferred Embodiments 1-21, whereinG is a group of formula

and R¹², R¹⁴, and R¹⁵ are independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R¹⁹, and halogen; R¹³ is chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, phenyl optionallysubstituted by 1-3 R¹⁹, C₃₋₇cycloalkyl optionally substituted by 1-3R¹⁹, 3-7 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹,5-6 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen, —CN,—C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴NR²²R²³,—NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, NR²⁴C(═O)OR²¹, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, —OC(═O)R²⁰, —S(═O)_(n)R²⁰,and —S(═O)₂NR R²³; or R¹² and R¹³ can, together with the atoms linkingthem, form a phenyl optionally substituted by 1-3 R¹⁹, C₃₋₇cycloalkyloptionally substituted by 1-3 R¹⁹, 3-7 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹ or a 5-10 membered heteroaryloptionally substituted by 1-6 R¹⁹.23. A compound as defined in any of preferred Embodiments 1-21, whereinG is a group of formula

and R¹² and R¹⁴ are H; R¹⁵ is chosen from H and halogen; R¹³ is chosenfrom H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, phenyl optionallysubstituted by 1-3 R¹⁹, 5-6 membered heteroaryl optionally substitutedby 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂,—NR²²R²³, —NR²⁴NR²²R²³, —NR²⁴OR²⁶, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰,—OC(═O)R²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³; or R¹² and R¹³ can,together with the atoms linking them, form a phenyl optionallysubstituted by 1-3 R¹⁹ or a 5-10 membered heteroaryl optionallysubstituted by 1-6 R¹⁹.24. A compound as defined in any of preferred Embodiments 1-21, whereinG is a group of formula

and R¹⁴ is H; R¹² and R¹⁵ are independently chosen from H and halogen;R¹³ is chosen from H, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)OR²¹,—NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, and —NR²⁴S(═O)₂NR²²R²³; or R¹² andR¹³ can, together with the atoms linking them, form a 5-6 memberedheteroaryl optionally substituted by 1-6 R¹⁹.25. A compound as defined in any of preferred Embodiments 1-21, whereinG is a group of formula

and R¹⁴ and R¹⁵ are H; R¹² is chosen from H and halogen; R¹³ is chosenfrom H, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together withthe atoms linking them, form a 5 membered heteroaryl optionallysubstituted by 1-2 R¹⁹.26. A compound as defined in any of preferred Embodiments 1-21, whereinG is a group of formula

and R¹⁴ is H; R¹² and R¹⁵ are independently chosen from H and halogen;R¹³ is chosen from H, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can,together with the atoms linking them, form a pyrrolyl ring optionallysubstituted by 1 R¹⁹.27. A compound as defined in any of preferred Embodiments 1-21, whereinG is a group of formula

and R¹², R¹³, R¹⁴, and R¹⁵ are H; or R¹² and R¹³, together with theatoms linking them, form a pyrrolyl ring.28. A compound as defined in any of preferred Embodiments 1-21, whereinG is a group of formula

and R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, C₆₋₁₀aryl optionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyloptionally substituted by 1-3 R¹⁹, 5-10 membered heteroaryl optionallysubstituted by 1-3 R¹⁹, halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰,—C(═O)NR²²R²³, —NO₂, —NR²²R²³, —NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³,—NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³, —OR²⁰, OC(═O)R²⁰, —OC(═O)NR²²R²³,—OC(═O)OR²⁰, —S(═O)_(n)R²⁰, and —S(═O)₂NR²²R²³.29. A compound as defined in any of preferred Embodiments 1-21, whereinG is a group of formula

and R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) areindependently chosen from H, C₁₋₆alkyl optionally substituted by 1-3R¹⁹, and benzyl optionally substituted by 1-3 R¹⁹.30. A compound as defined in any of preferred Embodiments 1-21, whereinG is a group of formula

and R^(a), R^(b), R^(c), R^(e), R^(f), R^(g), and R^(h) are H; and R^(d)is chosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, C₆₋₁₀aryloptionally substituted by 1-3 R¹⁹, C₇₋₁₁arylalkyl optionally substitutedby 1-3 R¹⁹, 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹,halogen, —CN, —C(═O)R²⁰, —C(═O)OR²⁰, —C(═O)NR²²R²³, —NO₂, —NR²²R²³,—NR²⁴C(═O)R²⁰, —NR²⁴C(═O)NR²²R²³, —NR²⁴S(═O)₂R²¹, —NR²⁴S(═O)₂NR²²R²³,—OR²⁰, OC(═O)R²⁰, —OC(═O)NR²²R²³, —OC(═O)OR²⁰, —S(═O)_(n)R²⁰, and—S(═O)₂NR²²R²³.31. A compound as defined in any of preferred Embodiments 1-21, whereinG is a group of formula

and R^(a), R^(b), R, R^(e), R^(f), R^(g), and R^(h) are H; and R^(d) ischosen from H, C₁₋₆alkyl optionally substituted by 1-3 R¹⁹, and benzyloptionally substituted by 1-3 R¹⁹.32. A compound as defined in any of preferred Embodiments 1-21, whereinG is a group of formula

and R^(a), R^(b), R, R^(d) R^(e), R^(f), R^(g), and R^(h) are H.33. A compound as defined in any of preferred Embodiments 1-32, whereinR¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R³⁹, C₂₋₆alkenyl optionally substituted by 1-3 R³⁹,C₂₋₆alkynyl optionally substituted by 1-3 R³⁹, C₆₋₁₀aryl optionallysubstituted by 1-3 R³⁹, C₇₋₁₁arylalkyl optionally substituted by 1-3R³⁹, C₃₋₆cycloalkyl optionally substituted by 1-3 R³⁹, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl optionally substituted by 1-3 R³⁹, halogen, —CN, —C(═O)R³⁰,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NO₂, —NR³²R³³, —NR³⁴C(═O)R³⁰,NR³⁴C(═O)NR³²R³³, —NR³⁴S(═O)₂R³¹, NR³⁴S(═O)₂NR³²R³³, —OR³⁰, ═O,—OC(═O)R³⁰, —OC(═O)NR³²R³³, —Si(R³⁴)₃, ═S, —S(═O)_(n)R³⁰, and—S(═O)₂NR³²R³³.34. A compound as defined in any of preferred Embodiments 1-32, whereinR¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl, C₆10aryl,C₇₋₁₁arylalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, 5-6membered heteroaryl, halogen, —C(═O)R³⁰, —C(═O)OR³⁰, —C(═O)NR³²R³³,—NR³²R³³, and —OR³⁰.35. A compound as defined in any of preferred Embodiments 1-32, whereinR¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl, phenyloptionally substituted by 1-3 R³⁹, C₃₋₆cycloalkyl, 3-6 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, 5-6 memberedheteroaryl, halogen, —C(═O)OR³⁰, NR³²R³³, and —OR³⁰36. A compound as defined in any of preferred Embodiments 1-32, whereinR¹⁹ at each occurrence is independently chosen from C₁₋₆alkyl optionallysubstituted by 1-3 R³⁹, C₂₋₆alkynyl, C₇₋₁₁arylalkyl optionallysubstituted by 1-3 R³⁹, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,5-6 membered heteroaryl, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³,—NR³⁴S(═O)₂R³¹, —OR³ and ═O.37. A compound as defined in any of preferred Embodiments 1-36, whereinR²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at eachoccurrence is independently chosen from H, C₁₋₆alkyl optionallysubstituted by 1-3 R⁴⁹, phenyl optionally substituted by 1-3 R⁴⁹, benzyloptionally substituted by 1-3 R⁴⁹, and C₃₋₆cycloalkyl optionallysubstituted by 1-3 R⁴⁹.38. A compound as defined in any of preferred Embodiments 1-36, whereinR²⁰ at each occurrence is independently chosen from H, C₁₋₆alkyloptionally substituted by 1-3 R⁴⁹, phenyl optionally substituted by 1-3R⁴⁹, benzyl optionally substituted by 1-3 R⁴⁹, C₃-6cycloalkyl, 3-6membered heterocycloalkyl, and 5-6 membered heteroaryl; R²¹, R²⁴, R²⁵,R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at each occurrence is H.39. A compound as defined in any of preferred Embodiments 1-36, whereinR²⁰, R²¹, R²⁴, R²⁵, R²⁶, R²⁷, R³⁰, R³¹, R³⁴, R³⁵, R³⁶ and R³⁷ at eachoccurrence is independently chosen from H and C₁₋₆alkyl.40. A compound as defined in any of preferred Embodiments 1-39, whereinR²², R²³, R³² and R³³ at each occurrence is independently chosen from H,C₁₋₆alkyl optionally substituted by 1-3 R⁵⁹, phenyl optionallysubstituted by 1-3 R⁵⁹, and 5-6 membered heteroaryl optionallysubstituted by 1-3 R⁵⁹.41. A compound as defined in any of preferred Embodiments 1-39, whereinR²² at each occurrence is independently chosen from H, C₁₋₆alkyl, phenyloptionally substituted by 1-3 R⁵⁹, and 5-6 membered heteroaryloptionally substituted by 1-3 R⁵⁹; R²³, R³² and R³³ at each occurrenceis independently chosen from H and C₁₋₆alkyl.42. A compound as defined in any of preferred Embodiments 1-39, whereinR²², R²³, R³² and R³³ at each occurrence is independently chosen from Hand C₁₋₆alkyl.43. A compound as defined in any of preferred Embodiments 1-42, whereinR³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R⁷⁹, phenyl optionallysubstituted by 1-3 R⁷⁹, benzyl optionally substituted by 1-3 R⁷⁹,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl,halogen, —CN, —C(═O)NR⁷²R⁷³, —NR⁷²R⁷³, —OR⁷⁰, and —S(═O)_(n)R⁷⁰.44. A compound as defined in any of preferred Embodiments 1-42, whereinR³⁹, R⁴⁹, R⁵⁹ and R⁶⁹ at each occurrence is independently chosen fromC₁₋₆alkyl optionally substituted by 1-3 R⁷⁹.45. A compound as defined in any of preferred Embodiments 1-44, whereinR⁷⁰, R⁷¹, R⁷⁴, R⁷⁵, R⁷⁶ and R⁷⁷ at each occurrence is independentlychosen from H and C₁₋₆alkyl optionally substituted by 1-3 R⁸⁹.46. A compound as defined in any of preferred Embodiments 1-44, whereinR⁷² and R⁷³ at each occurrence is independently chosen from H andC₁₋₆alkyl.47. A compound as defined in any of preferred Embodiments 1-46, whereinR⁷⁹ and R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently chosenfrom C₁₋₆alkyl and phenyl.48. A compound as defined in any of preferred Embodiments 1-46, whereinR⁷⁹, R⁸⁹, R⁹⁹ and R¹⁰⁹ at each occurrence is independently C₁₋₆alkyl.49. A compound as defined in any of preferred Embodiments 1 or 33-48,wherein X is chosen from —NHR²⁸ and 3-10 membered heterocycloalkylconsisting of carbon atoms and 1 or 2 nitrogen atoms in which theheterocycloalkyl is optionally substituted by 1-6 R¹⁹; R⁷ is chosen fromH, C₃₋₆cycloalkyl, and —OR²⁰; R⁸ is chosen from H and halogen; R⁹ ischosen from H, C₂₋₆alkynyl optionally substituted by 1-3 R¹⁹, phenyloptionally substituted by 1-3 R¹⁹, 3-6 membered heterocycloalkyloptionally substituted by 1-3 R¹⁹, 5, 6, or 9 membered heteroaryloptionally substituted by 1-3 R¹⁹, halogen, —NR²²R²³, —OR²⁰, and —SR²⁰;R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, C₇₋₁₆arylalkyloptionally substituted by 1-6 R¹⁹, 5-15 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, halogen, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² andR¹³ can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-6 R¹⁹, 3-15 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, or a 5-15 membered heteroaryloptionally substituted by 1-6 R¹⁹; and R^(a), R^(b), R^(c), R^(d),R^(e), R^(f), R^(g), and R^(h) are H.50. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NHR²⁸ and 5-10 membered heterocycloalkyl consisting ofcarbon atoms and 1 or 2 nitrogen atoms in which the heterocycloalkyl isoptionally substituted by 1-6 R¹⁹.51. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NHR²⁸ and 5-6 membered heterocycloalkyl consisting ofcarbon atoms and 1 or 2 nitrogen atoms in which the heterocycloalkyl isoptionally substituted by 1-6 R¹⁹.52. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NHR²⁸ and 5-10 membered heterocycloalkyl consisting ofcarbon atoms and 1 or 2 nitrogen atoms in which the heterocycloalkyl isoptionally substituted by 1 or 2 members chosen from C₁₋₆alkyloptionally substituted by 1-3 R³⁹, C₂₋₆alkynyl optionally substituted by1-3 R³⁹, C₆₋₁₁aryl optionally substituted by 1-3 R³⁹, C₇₋₁₆arylalkyloptionally substituted by 1-3 R³⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-3 R³⁹, 3-15 membered heterocycloalkyl optionallysubstituted by 1-3 R³⁹, halogen, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³,—NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰.53. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NHR²⁸ and 5-6 membered heterocycloalkyl consisting ofcarbon atoms and 1 or 2 nitrogen atoms in which the heterocycloalkyl isoptionally substituted by 1 or 2 members chosen from C₁₋₆alkyloptionally substituted by 1-6 halogen, halogen, —CN, —C(═O)OR³⁰,—C(═O)NR³²R, —NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰54. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NHR²⁸ and 5-6 membered heterocycloalkyl consisting ofcarbon atoms and 1 or 2 nitrogen atoms in which the heterocycloalkyl isoptionally substituted by 1 or 2 members chosen from C₁₋₆alkyloptionally substituted by 1-6 halogen, halogen, —CN, and —OH.55. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹),—NH(C₇₋₁₁arylalkyl optionally substituted by 1-6 R⁴), —NH(3-10 memberedheterocycloalkyl optionally substituted by 1-6 R⁴⁹), —NH(4-11 memberedheterocycloalkylalkyl optionally substituted by 1-6 R⁴⁹), and 3-10membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogenatoms in which the heterocycloalkyl is optionally substituted by 1-6R¹⁹.56. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹),—NH(C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁴⁹), —NH(5-6 memberedheterocycloalkyl), —NH(6-10 membered heterocycloalkylalkyl), and 5-10membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogenatoms in which the heterocycloalkyl is optionally substituted by 1-6R¹⁹.57. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹),—NH(C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁴⁹), —NH(5-6 memberedheterocycloalkyl), —NH(6-10 membered heterocycloalkylalkyl), and 5-6membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogenatoms in which the heterocycloalkyl is optionally substituted by 1-6R¹⁹.58. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹),—NH(C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁴⁹), —NH(5-6 memberedheterocycloalkyl), —NH(6-10 membered heterocycloalkylalkyl), and 5-10membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogenatoms in which the heterocycloalkyl is optionally substituted by 1 or 2members chosen from C₁₋₆alkyl optionally substituted by 1-3 R³⁹,C₂₋₆alkynyl optionally substituted by 1-3 R³⁹, C₆₋₁₁aryl optionallysubstituted by 1-3 R³⁹, C₇₋₁₆arylalkyl optionally substituted by 1-3R³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R³⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-3 R³⁹, halogen, —CN,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰.59. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹),—NH(C₇₋₁₁arylalkyl optionally substituted by 1-3 R⁴⁹), —NH(5-6 memberedheterocycloalkyl), —NH(6-10 membered heterocycloalkylalkyl), and 5-6membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogenatoms in which the heterocycloalkyl is optionally substituted by 1 or 2members chosen from C₁₋₆alkyl optionally substituted by 1-3 R³⁹,C₂₋₆alkynyl, C₆₋₁₁aryl, C₇₋₁₆arylalkyl optionally substituted by 1-3R³⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-3 R³⁹, 5-10 memberedheterocycloalkyl, halogen, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³,—NR³⁴C(═O)R³, and —OR³⁰.60. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(5-6membered heterocycloalkyl), —NH(6-10 membered heterocycloalkylalkyl),and 5-6 membered heterocycloalkyl consisting of carbon atoms and 1 or 2nitrogen atoms in which the heterocycloalkyl is optionally substitutedby 1 or 2 members chosen from C₁₋₆alkyl optionally substituted by 1-6halogen, halogen, —CN, —C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³,—NR³⁴C(═O)R³, and —OR³.61. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹),—NH(C₇₋₁₁arylalkyl), —NH(5-6 membered heterocycloalkyl consisting ofcarbon atoms and 1 or 2 nitrogen atoms), —NH(6-10 memberedheterocycloalkylalkyl consisting of carbon atoms and 1 or 2 nitrogenatoms), and 5-6 membered heterocycloalkyl consisting of carbon atoms and1 or 2 nitrogen atoms in which the heterocycloalkyl is optionallysubstituted by 1 or 2 members chosen from C₁-6alkyl optionallysubstituted by 1-3 R³⁹, C₂₋₆alkynyl, C₆₋₁₁aryl, C₇₋₁₆arylalkyloptionally substituted by 1-3 R³⁹, C₃₋₁₁cycloalkyl optionallysubstituted by 1-3 R³⁹, 5-10 membered heterocycloalkyl, halogen, —CN,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰.62. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹), —NH(5-6membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogenatoms), —NH(6-10 membered heterocycloalkylalkyl consisting of carbonatoms and 1 or 2 nitrogen atoms), and 5-6 membered heterocycloalkylconsisting of carbon atoms and 1 or 2 nitrogen atoms in which theheterocycloalkyl is optionally substituted by 1 or 2 members chosen fromC₁₋₆alkyl optionally substituted by 1-6 halogen, halogen, —CN,—C(═O)OR³⁰, —C(═O)NR³²R³³, —NR³²R³³, —NR³⁴C(═O)R³⁰, and —OR³⁰.63. A compound as defined in preferred Embodiment 49, wherein X ischosen from —NH(C₁₋₆alkyl optionally substituted by 1-6 R⁴⁹) and —NH(5-6membered heterocycloalkyl consisting of carbon atoms and 1 or 2 nitrogenatoms).64. A compound as defined in any of preferred Embodiments 1 or 33-63,wherein R⁷ is chosen from H, C₃-6cycloalkyl, and —O(C₁₋₆alkyl); R⁸ ischosen from H and halogen; and R⁹ is chosen from H, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5,6, or 9 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen,—NR²²R²³, —OR²⁰, and —SR²⁰.65. A compound as defined in any of preferred Embodiments 1 or 33-63,wherein R⁷ is chosen from H, C₃-6cycloalkyl, and —OR²⁰; R⁸ is H; and R⁹is H.66. A compound as defined in any of preferred Embodiments 1 or 33-63,wherein R⁷ is chosen from H, C₃-6cycloalkyl, and —O(C₁₋₆alkyl); R⁸ is H;and R⁹ is H.67. A compound as defined in any of preferred Embodiments 1 or 33-63,wherein R⁷ is chosen from H, cyclopropyl, and —O(C₁₋₆alkyl); R⁸ ischosen from H and halogen; and R⁹ is chosen from H, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5,6, or 9 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen,—NR²²R²³, —OR²⁰, and —SR²⁰.68. A compound as defined in any of preferred Embodiments 1 or 33-63,wherein R⁷ is chosen from H, cyclopropyl, and —O(C₁₋₆alkyl); R⁸ is H;and R⁹ is H.69. A compound as defined in any of preferred Embodiments 1 or 33-63,wherein R⁷ is chosen from H, cyclopropyl, and —O(CH₃); R⁸ is H; and R⁹is H.70. A compound as defined in any of preferred Embodiments 1 or 33-63,wherein R⁷ is chosen from H, cyclopropyl, and —O(C₁₋₆alkyl); R⁸ ischosen from H and halogen; and R⁹ is chosen from H, C₂₋₆alkynyloptionally substituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3R¹⁹, 3-6 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5,6, or 9 membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen,—NR²²R²³, —OR²⁰, and —SR²⁰.71. A compound as defined in any of preferred Embodiments 1 or 33-63,wherein R⁷ is chosen from H, C₃₋₆cycloalkyl, and —O(CH₃); R⁸ is chosenfrom H and halogen; and R⁹ is chosen from H, C₂₋₆alkynyl optionallysubstituted by 1-3 R¹⁹, phenyl optionally substituted by 1-3 R¹⁹, 3-6membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, 5, 6, or 9membered heteroaryl optionally substituted by 1-3 R¹⁹, halogen,—NR²²R²³, —OR²⁰, and —SR²⁰.72. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴ and R¹⁵ are H, and R¹³ is chosen from H, C₇₋₁₆arylalkyloptionally substituted by 1-6 R¹⁹, 5-10 membered heteroaryl optionallysubstituted by 1-6 R¹⁹, halogen, —NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² andR¹³ can, together with the atoms linking them, form a C₆₋₁₁aryloptionally substituted by 1-6 R¹⁹, 5-10 membered heterocycloalkyloptionally substituted by 1-6 R¹⁹, or a 5-10 membered heteroaryloptionally substituted by 1-6 R¹⁹.73. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H,C₇₋₁₆arylalkyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹, halogen, —NR²²R²³, and—NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, or a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹.74. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴ and R¹⁵ are H, and R¹³ is chosen from H, halogen,—NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atomslinking them, form a C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, 5-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹, or a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹.75. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, halogen,—NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atomslinking them, form a phenyl optionally substituted by 1-3 R¹⁹, 5-10membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ in which theheterocycloalkyl contains carbon atoms and 1 or 2 nitrogen atoms, or a5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹ in which theheteroaryl contains carbon atoms and 1 or 2 nitrogen atoms.76. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, halogen,—NR²²R²³, and —NR²⁴C(═O)R²⁰; or R¹² and R¹³, can, together with theatoms linking them, form a phenyl optionally substituted by 1-3 R¹⁹,5-10 membered heterocycloalkyl optionally substituted by 1-3 R¹⁹ inwhich the heterocycloalkyl contains carbon atoms and 1 nitrogen atom, ora 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹ in whichthe heteroaryl contains carbon atoms and 1 nitrogen atom.77. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NR²²R²³, and—NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a phenyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ in which theheterocycloalkyl contains carbon atoms and 1 or 2 nitrogen atoms, or a5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹ in which theheteroaryl contains carbon atoms and 1 or 2 nitrogen atoms.78. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NR²²R²³, and—NR²⁴C(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a phenyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ in which theheterocycloalkyl contains carbon atoms and 1 nitrogen atom, or a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹ in which theheteroaryl contains carbon atoms and 1 nitrogen atom.79. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NHR²³, and—NHC(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a C₆₋₁₁aryl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹, or a 5-10 memberedheteroaryl optionally substituted by 1-3 R¹⁹.80. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NHR²³, and—NHC(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a phenyl optionally substituted by 1-3 R¹⁹, 5-10 memberedheterocycloalkyl optionally substituted by 1-3 R¹⁹ in which theheterocycloalkyl contains carbon atoms and 1 or 2 nitrogen atoms, or a5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹ in which theheteroaryl contains carbon atoms and 1 or 2 nitrogen atoms.81. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NHR²³, and—NHC(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹.82. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NHR²³, and—NHC(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹ inwhich the heteroaryl contains carbon atoms and 1 or 2 nitrogen atoms.83. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H, —NHR²³, and—NHC(═O)R²⁰; or R¹² and R¹³ can, together with the atoms linking them,form a 5-10 membered heteroaryl optionally substituted by 1-3 R¹⁹ inwhich the heteroaryl contains carbon atoms and 1 nitrogen atom.84. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H and —NHR²³; orR¹² and R¹³ can, together with the atoms linking them, form a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹.85. A compound as defined in any of preferred Embodiments 1 or 33-71,wherein R¹², R¹⁴, and R¹⁵ are H, and R¹³ is chosen from H and —NHR²³; orR¹² and R¹³ can, together with the atoms linking them, form a 5-10membered heteroaryl optionally substituted by 1-3 R¹⁹ in which theheteroaryl contains carbon atoms and 1 or 2 nitrogen atoms.86. A compound chosen from:

-   1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   (5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine;-   N-(2-aminoethyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2R)-2-aminopropyl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-aminopropyl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   (3R)—N-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]pyrrolidin-3-amine;-   (3R)—N-[2-(3-fluoropyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]pyrrolidin-3-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-2-(3-fluoropyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-6-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   1-[6-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   (3S)-3-benzyl-1-[6-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   (2S)-1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-ol;-   (3    S)-3-benzyl-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   (3R)-3-benzyl-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   1-methyl-4-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   1-methyl-4-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-1,4-diazepane;-   (2S)-2,4-dibenzyl-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   4-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]morpholine;-   tert-butyl    4-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate;-   tert-butyl    4-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-1,4-diazepane-1-carboxylate;-   4-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]thiomorpholine;-   N,N-Dimethyl[(2S)-1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-yl]amine;-   N-[(2S)-2-amino-3-phenylpropyl]-N-methyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   4-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-one;-   N-[(2S)-1-amino-3-phenylpropan-2-yl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   (2R)-2-benzyl-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   (3    S)-3-benzyl-1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   1-[8-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-1,4-diazepane;-   2-{4-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl}ethan-1-ol;-   (3    S)-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]pyrrolidin-3-ol;-   (3R)-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]pyrrolidin-3-ol;-   (3R)-3-benzyl-1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   (2    S)-2-benzyl-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   methyl    (2S,4S)-4-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}pyrrolidine-2-carboxylate;-   methyl    (2S,4S)-4-[(2S,4S)-4-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}pyrrolidine-2-amido]pyrrolidine-2-carboxylate;-   [(2S)-1-{[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}-3-phenylpropan-2-yl](methyl)amine;-   N-[(3R)-oxolan-3-yl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-3-(trifluoromethyl)piperazine;-   (3    S)-1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-3-methylpiperazine;-   (3R)-1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]pyrrolidin-3-amine;-   [(2R)-4-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]methanol;-   N-[(2R,3R)-2-amino-3-fluoro-3-phenylpropyl]-5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   2-[(2S)-2-benzyl-4-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]acetamide;-   [(2S)-1-{[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}-3-phenylpropan-2-yl]dimethylamine;-   (3    S)-1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]pyrrolidin-3-ol;-   1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-3,5-cis-dimethylpiperazine;-   (3R)-1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-3-methylpiperazine;-   (3    S)-1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]pyrrolidin-3-amine;-   3-(fluoromethyl)-1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   N-(propan-2-yl)-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperidine-4-carboxamide;-   4-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxamide;-   N-cyclohexyl-4-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxamide;-   2-{4-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl}acetonitrile;-   1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-3-(trifluoromethyl)piperazine;-   1-[8-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-3-(trifluoromethyl)piperazine;-   (3S)-3-ethyl-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   (3    S)-3-(propan-2-yl)-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   1-[2-(3-fluoropyridin-4-yl)-5-methoxypyrido[3,4-d]pyrimidin-4-yl]piperazine;-   4-{4-[(8aR)-octahydropyrrolo[1,2-a]piperazin-2-yl]pyrido[3,4-d]pyrimidin-2-yl}pyridine;-   1-[2-(3-fluoropyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   1-[2-(3-fluoropyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-3-(trifluoromethyl)piperazine;-   4-{4-[(3aS)-octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl]pyrido[3,4-d]pyrimidin-2-yl}pyridine;-   (3S)-3-benzyl-1-[8-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   3-phenyl-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   4-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]morpholine;-   3-ethynyl-1-[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   2-benzyl-4-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]morpholine;-   {1-[8-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]azetidin-3-yl}methanol;-   (3R)-3-[fluoro(phenyl)methyl]-1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   1-[8-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperidin-4-ol;-   (3R)-3-[fluoro(phenyl)methyl]-1-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   (4-fluorophenyl)[(2R)-4-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]methanol;-   N—[(S)-1-Benzyl-2-(2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-formamide;-   N—[(S)-1-Benzyl-2-(2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-ethyl]-acetamide;-   methyl    [(2S)-1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-yl]amine;-   (2S)-2-benzyl-4-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-1-methylpiperazine;-   2-{[(2S)-1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-yl]amino}acetamide;-   N-(1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-yl)methanesulfonamide;-   (1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-yl)urea;-   3-ethyl-1-(1-phenyl-3-{[2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}propan-2-yl)urea;-   (3aR)-5-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-1-one;-   2-{4-[5-methoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl}acetonitrile;-   N-{3-[4-((S)-2-Amino-3-phenyl-propylamino)-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-8-yl]-phenyl}-methanesulfonamide;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(1H-pyrazol-5-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-phenyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   4-(4-{[(2S)-2-amino-3-phenylpropyl]amino}-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-8-yl)phenol;-   3-(4-{[(2S)-2-amino-3-phenylpropyl]amino}-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-8-yl)phenol;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(2-methoxyphenyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(3-methoxyphenyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(4-methoxyphenyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(2-chlorophenyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(1-benzofuran-5-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(1-methyl-1H-pyrazol-4-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(pyridin-3-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-2,8-bis(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(3-chlorophenyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(4-chlorophenyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(1-methyl-1H-pyrazol-5-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   2-(4-{[(2S)-2-amino-3-phenylpropyl]amino}-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-8-yl)phenol;-   N-[(2S)-2-amino-3-phenylpropyl]-8-[3-(3-chlorophenyl)phenyl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-[4-(4-chlorophenyl)phenyl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-2-(pyridin-4-yl)-8-(pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(3-aminophenyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(1-benzofuran-7-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(5-methylthiophen-2-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(dimethyl-1,2-oxazol-4-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(furan-3-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-2-(pyridin-4-yl)-8-(thiophen-3-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(furan-2-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(1H-1,3-benzodiazol-5-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(3-ethoxyphenyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(2-methylphenyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(3-methylphenyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-[3-(1H-pyrazol-5-yl)phenyl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-[5-(aminomethyl)furan-2-yl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   (R)-3-Phenyl-N-(2-pyridin-4-yl-8-pyridin-2-yl-pyrido[3,4-d]pyrimidin-4-yl)-propane-1,2-diamine;-   N⁴—((R)-2-Amino-3-phenyl-propyl)-N⁸-phenyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine-4,8-diamine;-   4-N-[(2S)-2-amino-3-phenylpropyl]-2-(pyridin-4-yl)-8-N-(pyrimidin-2-yl)pyrido[3,4-d]pyrimidine-4,8-diamine;-   4-N-[(2S)-2-amino-3-phenylpropyl]-8-N-(3-chlorophenyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine-4,8-diamine;-   4-N-[(2S)-2-amino-3-phenylpropyl]-2-(pyridin-4-yl)-8-N-(1H-1,2,4-triazol-3-yl)pyrido[3,4-d]pyrimidine-4,8-diamine;-   (R)—N-[8-(4-Methyl-piperazin-1-yl)-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl]-3-phenyl-propane-1    1,2-diamine;-   (R)-3-Phenyl-N¹-(8-phenylsulfanyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-propane-1,2-diamine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-phenoxy-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   N-[(2S)-2-amino-3-phenylpropyl]-8-(methylsulfanyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   4-(4-{[(2S)-2-amino-3-phenylpropyl]amino}-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-8-yl)-2-methylbut-3-yn-2-ol;-   5-Chloro-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine;-   1-[5-bromo-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   1-[5,8-dichloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   5-Butyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine;-   1-[5-ethyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   N-[(2S)-2-amino-3-phenylpropyl]-5-ethyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;-   1-[5-methyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   1-[5-cyclopropyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl]piperazine;-   1-{5-[(benzyloxy)methyl]-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl}piperazine;-   5-Chloro-4-piperazin-1-yl-8-(1H-pyrazol-3-yl)-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine;-   5-chloro-N,N-dimethyl-4-(piperazin-1-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-8-amine;-   5-Isopropenyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine;-   5-Methoxy-4-piperidin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine;-   3-Amino-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidine-3-carboxylic    acid amide;-   3-Amino-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidine-3-carboxylic    acid phenylamide;-   4-Amino-1-(5-methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperidine-4-carboxylic    acid;-   [(S)-1-(4-chloro-phenyl)-3-hydroxy-propyl]-amide;-   4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-2-carboxylic    acid methyl ester;-   4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-2-carboxylic    acid phenylamide;-   4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-2-carboxylic    acid benzylamide;-   4-(5-Methoxy-2-pyridin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazine-2-carboxylic    acid phenethyl-amide;-   4-Piperazin-1-yl-8-propyl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine;-   8-Methyl-4-piperazin-1-yl-2-pyridin-4-yl-pyrido[3,4-d]pyrimidine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrazin-2-yl-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-trifluoromethyl-oxazol-2-yl)-amine;-   (4,5-Dimethyl-oxazol-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (4-Cyclopropyl-thiazol-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   3-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-benzonitrile;-   (2-Fluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-trifluoromethyl-phenyl)-amine;-   4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamine;-   N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-morpholin-4-yl-acetamide;-   N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-piperidin-1-yl-acetamide;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrimidin-4-yl-amine;-   N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-benzamide;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-methyl-amine;-   N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide;-   N-{4-[4-(4-Hydroxy-piperidin-1l-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   Cyclopropanecarboxylic acid    [4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amide;-   N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2,2-dimethyl-propionamide;-   Tetrahydro-pyran-4-carboxylic    acid[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amide;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-thiazol-2-yl-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-oxazol-2-yl-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methyl-oxazol-2-yl)-amine;-   {(S)-4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-yl}-methanol;-   1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-4-methyl-piperidin-4-ol;-   {4-[4-((S)-3-Isopropyl-piperazin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   2-{(S)-4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-yl}-ethanol;-   N-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-N′,N′-dimethyl-benzene-1,4-diamine;-   {5-Methoxy-2-[2-(3-morpholin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {2-[2-(2-Fluoro-phenylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {5-Methoxy-2-[2-(4-morpholin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {2-[2-(4-Fluoro-phenylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {4-[5-Methoxy-4-(3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   {(S)-4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-yl}-acetonitrile;-   {4-[4-((R)-3-Fluoromethyl-piperazin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]pyridin-2-yl}-phenyl-amine;-   Cyclopropanecarboxylic acid    {4-[4-(4-hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-amide;-   {4-[4-((S)-3-Fluoromethyl-piperazin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   {4-[4-((S)-3-Cyclopropyl-piperazin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   {4-[4-((R)-3-Fluoromethyl-piperazin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2yl]-pyridin-2-yl}-(2,3,6-trifluoro-phenyl)-amine;-   [5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine;-   {5-Methoxy-2-[2-(pyrazin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   Thiophene-2-carboxylic acid    {4-[5-methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-amide;-   Cyclopentyl-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   Cyclohexyl-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   {2-[2-(Pyrazin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol;-   2-{3-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-R-pyrrolidin-1-yl}-acetamide;-   [4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine;-   [4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-phenyl)-amine;-   (2-Fluoro-phenyl)-{2-[2-(2-fluoro-phenylamino)-pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-5-yl}-amine;-   4-{5-(4-Cyano-pyridin-2-ylamino)-2-[2-(4-cyano-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperazine;-   {4-[5-Chloro-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   N-[4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide;-   [4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3-difluoro-phenyl)-amine;-   [4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-fluoro-pyridin-2-yl)-amine;-   [4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-phenyl)-amine;-   [4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4-difluoro-phenyl)-amine;-   [4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine;-   [4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3,6-trifluoro-phenyl)-amine;-   [4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-fluoro-pyridin-2-yl)-amine;-   [4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-trifluoromethyl-pyridin-2-yl)-amine;-   5-[4-(5-Chloro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-pyridine-2-carbonitrile;-   {4-Piperazin-1-yl-2-[2-(2,3,6-trifluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-5-yl}-(2,3,6-trifluoro-phenyl)-amine;-   (2,6-Difluoro-phenyl)-{2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-5-yl}-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-phenyl)-amine;-   2-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinonitrile;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3,6-trifluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-(3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(6-fluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-trifluoromethyl-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-fluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4,5-dimethyl-oxazol-2-yl)-amine;-   {4-[5-Cyclopropyl-4-((S)-3-cyclopropyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   1-{5-Cyclopropyl-2-[2-(2-fluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ol;-   {4-[5-Cyclopropyl-4-((S)-3-isopropyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   {4-[5-Cyclopropyl-4-((S)-3-cyclopropyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2-fluoro-phenyl)-amine;-   {4-[5-Cyclopropyl-4-((S)-3-cyclopropyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(6-fluoro-pyridin-2-yl)-amine;-   (4-{5-Cyclopropyl-4-[3-(1,1-difluoro-ethyl)-piperazin-1-yl]-pyrido[3,4-d]pyrimidin-2-yl}-pyridin-2-yl)-phenyl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine;-   {(S)-4-[5-Cyclopropyl-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-yl}-acetonitrile;-   Cyclopentyl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   Cyclohexyl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(tetrahydro-pyran-4-yl)-amine;-   Cyclopentyl-{4-[5-cyclopropyl-4-(3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-amine;-   Adamantan-1-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   2-Amino-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-benzamide;-   4-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-benzamide;-   4-Amino-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-benzamide;-   {4-[(1S,4S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   Pyrazine-2-carboxylic acid    {4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-amide;-   3-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-benzamide;-   3-Amino-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-benzamide;-   2-(4-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenoxy)-acetamide;-   2-(3-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenoxy)-acetamide;-   2-(4-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamide;-   2-(4-Amino-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   2-(3-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamide;-   2-(3-Amino-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   {2-[2-(5-Phenyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {2-[2-(6-Morpholin-4-yl-pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   (2-{2-[6-(4-Methyl-piperazin-1-yl)-pyridin-3-ylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine;-   2-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   {2-[2-(4-Imidazol-1-ylmethyl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   2-(3-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenoxy)-acetamide;-   2-(3-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamide;-   2-(3-Amino-phenyl)-N-{4-[5-methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   2-(4-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-acetamide;-   2-(4-Amino-phenyl)-N-{4-[5-methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   1-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile;-   {5-Methoxy-2-[2-(5-phenyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {5-Methoxy-2-[2-(6-morpholin-4-yl-pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   (5-Methoxy-2-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine;-   2-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   {2-[2-(4-Imidazol-1-ylmethyl-phenylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   2-Phenyl-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   2-(4-Methoxy-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   2-(2-Methoxy-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   2-(3-Methoxy-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   {2-[2-(4-Methyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {2-[2-(4-Chloro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   6-{4-[4-((R)-Pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-nicotinonitrile;-   2-[4-(4-Piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinonitrile;-   {2-[2-(4-Morpholin-4-yl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   6-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-nicotinonitrile;-   {2-[2-(5-Methyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {2-[2-(5-Chloro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   2-[2-(Pyrimidin-4-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   2-(3-Cyano-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   2-(4-Cyano-phenyl)-N-{4-[4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   (R)-Pyrrolidin-3-yl-{2-[2-(4-trifluoromethyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-amine;-   (R)-Pyrrolidin-3-yl-{2-[2-(5-trifluoromethyl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-amine;-   2-[4-(5-Methoxy-4-piperazin-1-yl-yl-pyrid[3,4-d]pyriidin-2-yl)-pyridin-2-ylamino]-isonicotinonitrile;-   6-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-nicotinonitrile;-   {4-[5-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   2-(4-Cyano-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide;-   2-(3-Cyano-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide;-   {2-[2-(5-Morpholin-4-yl-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {2-[2-(2-Methoxy-4-morpholin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   (2-Methoxy-4-morpholin-4-yl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   {5-Methoxy-2-[2-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   (5-Methoxy-2-{2-[4-(tetrahydro-pyran-4-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[4-(tetrahydro-pyran-4-yl)-phenyl]-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methyl-pyridin-2-yl)-amine;-   (4-Chloro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (5-Chloro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-trifluoromethyl-pyridin-2-yl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;-   2-(4-Chloro-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide;-   2-(3-Chloro-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide;-   N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-phenyl-acetamide;-   2-(3-Methoxy-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide;-   N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-(3-trifluoromethyl-phenyl)-acetamide;-   2-(4-Methoxy-phenyl)-N-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-morpholin-4-yl-pyridin-3-yl)-amine;-   {2-[2-(Pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {5-Methoxy-2-[2-(pyridin-3-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyridin-3-yl-amine;-   2-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinamide;-   6-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-nicotinamide;-   (3-Methoxy-4-morpholin-4-yl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-methyl-4-morpholin-4-yl-phenyl)-amine;-   5-[4-(5-Methoxy-4-piperazin-1-yl-pyrid[3,4-d]pyrimidin-yl-pyridpyridin-2-ylamino]-pyridine-2-carbonitrile;-   {5-Methoxy-2-[2-(pyrimidin-5-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrimidin-5-yl-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrimidin-5-yl-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyridin-2-yl-amine;-   2-[4-(5-Methoxy-4-morpholin-4-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-isonicotinonitrile;-   2-(3-Cyano-phenyl)-N-[4-(5-methoxy-4-morpholin-4-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine;-   N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-(4-trifluoromethyl-phenyl)-acetamide;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-phenyl-pyridin-3-yl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;-   N-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-2-pyridin-3-yl-acetamide;-   2-{4-[5-Methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   2-(3-Chloro-phenyl)-N-{4-[5-methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-pyridin-3-yl-acetamide;-   N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-pyridin-4-yl-acetamide;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methoxy-pyridin-2-yl)-amine;-   2-{4-[4-(4-Hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isoncotinonitrile;-   2-(3-Cyano-phenyl)-N-{4-[4-(4-hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   2-(3-Cyano-phenyl)-N-{4-[5-methoxy-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   (6-Chloro-pyridin-3-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (R)—N-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-2-phenyl-propionamide;-   (S)—N-{4-[5-Methoxy-4-((R)-pyrrolidin-3-ylamino)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-2-phenyl-propionamide;-   (R)—N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-phenyl-propionamide;-   (S)—N-[4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-phenyl-propionamide;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-methyl-pyridin-2-yl)-amine;-   (3-Fluoro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-piperazin-1-ylpyridin-3-yl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[2-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-piperidin-4-yl-1H-pyrazol-4-yl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methyl-pyridin-3-yl)-amine;-   (5-Chloro-pyridin-3-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (2-Fluoro-4-morpholin-4-yl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   3-Fluoro-4-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-benzonitrile;-   4-Fluoro-3-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-benzonitrile;-   (2,6-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (2-Fluoro-6-methyl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrimidin-2-yl-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methoxy-pyridin-3-yl)-amine;-   (S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-3-ol;-   2-{4-[4-((S)-3-Hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol;-   (R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-3-ol;-   2-{4-[4-((R)-3-Hydroxy-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   [5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(S)-1-pyrrolidin-2-ylmethyl-amine;-   [5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-1-pyrrolidin-2-ylmethyl-amine;-   2-{4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-1-yl}-ethanol;-   {1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-azetidin-3-yl}-methanol;-   {(R)-4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-yl}-methanol;-   (R)-7-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-hexahydro-oxazolo[3,4-a]pyrazin-3-one;-   (−)-cis-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol;-   (1)-trans-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol;-   4-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-one;-   (2,3-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (2,5-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-yl-pyrid[3,4-d]pyriidin-2-y)-pyridin-2-yl]-(2,4,6-trifluoro-phenyl)-amine;-   ((R)-4-{2-[2-(2,6-Difluoro-phenylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-piperazin-2-yl)-methanol;-   3-Hydroxymethyl-1-[5-methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrid[3,4-d]pyrimidin-yl)-pyridpyridin-2-yl]-(2,3,6-trifluoro-phenyl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-trifluoromethyl-phenyl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-trifluoromethyl-phenyl)-amine;-   (6-Fluoro-pyridin-2-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methoxy-pyridin-2-yl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-2-yl)-amine;-   (2-Fluoro-pyridin-3-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (2-Fluoro-3-methyl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (2-Fluoro-3-trifluoromethyl-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (2,4-Difluoro-phenyl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-yl-pyrid[3,4-d]pyriidin-2-y)-pyridin-2-yl]-(2,3,4-trifluoro-phenyl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-yl-pyrid[3,4-d]pyriidin-2-y)-pyridin-2-yl]-(2,4,5-trifluoro-phenyl)-amine;-   (3S,4S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol;-   (3R,4R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol;-   3-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ylamino]-propionamide;-   [4-(5-Methoxy-4-piperidin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine;-   {4-[4-(4,4-Difluoro-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-4-carbonitrile;-   {4-[4-(4-Fluoro-piperidin-1-yl)-5-methoxy-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   (3R,4S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol;-   (3S,4R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol;-   {(R)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanol;-   {(S)-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-methanol;-   (meso)-cis-1-[5-Methoxy-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-azepane-4,5-diol;-   1-{2-[2-(6-Fluoro-pyridin-2-ylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ol;-   1-{5-Methoxy-2-[2-(6-methoxy-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ol;-   ((S)-1-{2-[2-(6-Fluoro-pyridin-2-ylamino)-pyridin-4-yl]-5-methoxy-pyrido[3,4-d]pyrimidin-4-yl}-pyrrolidin-3-yl)-methanol;-   ((S)-1-{5-Methoxy-2-[2-(6-methoxy-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-pyrrolidin-3-yl)-methanol;-   2-(4-Cyano-phenyl)-N-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide;-   [4-(5-Cyclopropyl-4-piperazin-1-yl[3,4-d]pymdn-2-yl)-pyridin-2-yl]-(2-methyl-4-morpholin-4-yl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-morpholin-4-yl-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyridin-3-yl-amine;-   (2-Chloro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-methyl-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine;-   2-{4-[5-Cyclopropyl-4-(4-hydroxy-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-fluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-phenyl)-amine;-   (±)-2-{4-[5-Cyclopropyl-4-cis-3,4-dihydroxy-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-o-tolyl-amine;-   2-{4-[5-Cyclopropyl-4-((3R,4S)-3,4-dihydroxy-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   2-{4-[5-Cyclopropyl-4-((3S,4R)-3,4-dihydroxy-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-N-(1-phenylpyrazol-4-yl)pyridin-2-amine;-   (2,3-Dimethyl-2H-indazol-6-yl)-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,    4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [1-(2-Fluoro-phenyl)-1H-pyrazol-4-yl]-[4-(5-methoxy-4-piperazin-1-yl-pyrido[3,    4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-cyclopropyl-4-piperazin-1-yl-pydo[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-phenyl-1H-pyrazol-4-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3-dimethyl-2H-indazol-6-yl)-amine;-   Phenyl-[4-(4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-pyridin-3-yl)-amine;-   [4-(5-Methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methyl-isoxazol-3-yl)-amine;-   2-[2-(3-Piperazin-1-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-ol;-   2-[2-(3-Piperazin-1-ylmethyl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-ol;-   2-[2-(1-Piperidin-4-ylmethyl-1H-pyrazol-4-ylamino)-pyridin-4-yl]-pyrido[3,    4-d]pyrimidin-4-ol;-   {5-Methoxy-2-[2-(3-piperazin-1-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-amine;-   (5-Methoxy-2-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-methyl-amine;-   {5-Methoxy-2-[2-(3-piperidin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-amine;-   [4-(5-Methoxy-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-piperazin-1-yl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-5-methyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,5-dimethyl-phenyl)-amine;-   5-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-pyridine-2-carbonitrile;-   4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrazin-2-yl-amine;-   Cyclopropyl-{4-[5-cyclopropyl-4-(3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(R)-tetrahydro-furan-3-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4,4-difluoro-cyclohexyl)-amine;-   {4-[5-Cyclopropyl-4-((R)-3-fluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(4-trifluoromethyl-pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-((R)-3-fluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(6-fluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-methoxy-pyridin-3-yl)-amine;-   (6-Chloro-pyridin-2-yl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-methoxy-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-trifluoromethyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-methoxymethyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pydo[3,4-d]pymdn-2-yl)-pyridin-2-yl]-(S)-tetrahydro-furan-3-yl-amine;-   2-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-benzonitrile;-   tert-Butyl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,5-difluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-5-trifluoromethyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-fluoro-2-methyl-phenyl)-amine;-   3-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-4-methyl-benzonitrile;-   7-[5-Cyclopropyl-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-hexahydro-oxazolo[3,4-a]pyrazin-3-one;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-fluoro-pyridin-2-yl)-amine;-   (2-Chloro-6-methyl-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   3-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-4-fluoro-benzonitrile;-   (4-tert-Butyl-2-chloro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   2-{4-[5-Cyclopropyl-4-((R)-3-fluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   {4-[5-Cyclopropyl-4-((R)-3-fluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2-fluoro-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,2,2-trifluoro-ethyl)-amine;-   2-{4-[5-Cyclopropyl-4-(3-oxo-tetrahydro-oxazolo[3,4-a]pyrazin-7-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-fluoro-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-trifluoromethyl-pyridin-3-yl)-amine;-   {4-[5-Cyclopropyl-4-(2,5-diaza-bicyclo[4.1.0]hept-2-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   {4-[5-Cyclopropyl-4-(2,5-diaza-bicyclo[4.1.0.]hept-2-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-dichloro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3-dimethyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-dimethyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3-dichloro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3-dichloro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-methyl-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyridazin-3-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,6-difluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[4-(dimethyl-phosphinoyl)-phenyl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[4-(diethyl-phosphinoyl)-phenyl]-amine;-   N⁵-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-N²,N²-dimethyl-pyridine-2,    5-diamine;-   {4-[5-Cyclopropyl-4-((R)-3-fluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-methoxy-2-methyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-methyl-5-trifluoromethyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-5-trifluoromethoxy-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-5-methanesulfonyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-3-methyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-isopropyl-2-methyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pent-deuterio-phenyl-amine;-   1-{2-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-phenyl}-ethanol;-   (1R,2S)-2-Amino-cyclopentanecarboxylic acid    [4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amide;-   1-{4-[2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-yl}-cyclopropanol;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-yl-pyridin-2-yl]-pyrazolo[1,5-a]pyridin-6-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-yl-pyridin-2-yl]-pyrazolo[1,5-a]pyridin-5-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-trifluoromethyl-pyridazin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-3-methoxy-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-ethoxy-2,6-difluoro-phenyl)-amine;-   (2-Chloro-3-methyl-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   {4-[5-Cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   (2-Chloro-4-fluoro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-methoxy-phenyl)-amine;-   (2-Chloro-4-methyl-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4-dimethyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-3-methyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-4-methyl-phenyl)-amine;-   (2-Chloro-5-fluoro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (2-Chloro-5-methyl-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (2-Chloro-3-fluoro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   5-Cyclopropyl-2-(6,7-dimethoxy-quinolin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-5-methoxy-phenyl)-amine;-   N-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-acetamide;-   4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamine;-   N-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-isobutyramide;-   Cyclopropanecarboxylic acid    [4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amide;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,3-difluoro-cyclobutyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-((R)-1-phenyl-ethyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-((S)-1-phenyl-ethyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-methoxy-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-3-methoxy-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-4-methoxy-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrdo[34-d]pymdn-2-yl)-pyridin-2-yl]-(3-methoxy-2-methyl-phenyl)-amine;-   (2-Chloro-5-methoxy-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-fluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-trifluoromethyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-trifluoromethyl-phenyl)-amine;-   (2-Chloro-5-trifluoromethyl-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,4-difluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-methyl-1H-pyrazol-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-fluoro-cyclohexyl)-amine;-   (+/−)-(cis)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-piperidine-3,4-diol;-   (4-Cyclopropyl-2,6-difluoro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-4-methyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-methyl-1H-imidazol-4-yl)-amine;-   2-{4-[5-Cyclopropyl-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-1-yl}-ethanol;-   (S)-3-{4-[5-Cyclopropyl-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-1-yl}-propane-1,2-diol;-   (R)-3-{4-[5-Cyclopropyl-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-1-yl}-propane-1,2-diol;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyridin-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-methoxy-4-methyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,4-dimethoxy-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine;-   N-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-phenyl-acetamide;-   N-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-3,3,3-trifluoro-propionamide;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[4-(1-methyl-4-oxo-42⁵-[1,4]azaphosphinan-4-yl)-phenyl]-amine;-   2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-4-[3-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-pyrido[3,4-d]pyrimidine;-   (2-Chloro-6-fluoro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (6-Chloro-2-fluoro-3-methyl-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (3-Chloro-2,6-difluoro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,3-difluoro-cyclopentyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-isopropyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-ethyl-phenyl)-amine;-   2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-4-(3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[4-(1-ethyl-4-oxo-4λ⁵-[1,4]azaphosphinan-4-yl)-2-methoxy-phenyl]-amine;-   N-(4-{5-Cyclopropyl-4-[3-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-pyrido[3,4-d]pyrimidin-2-yl}-pyridin-2-yl)-acetamide;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-fluoro-3-methoxy-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4-difluoro-5-methoxy-phenyl)-amine;-   Cyclopropylmethyl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-methyl-amine;-   4-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-2-fluoro-benzonitrile;-   [4-(5-Cyclopropyl-4-[1,4]diazepan-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenyl-amine;-   4-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-cyclohexanol;-   (2-Chloro-6-fluoro-3-methoxy-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (2-Chloro-3,6-difluoro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   {4-[5-Cyclopropyl-4-(2,2,3,3,5,5,    6,6-octadeuterio-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   (4-Cyclopropyl-3-methoxy-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   4-[5-Cyclopropyl-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylic    acidamide;-   N-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2-(2,6-difluoro-phenyl)-acetamide;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-5-propyl-phenyl)-amine;-   (4-Cyclopropyl-2-fluoro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (4-{5-Cyclopropyl-4-[3-(2,2,2-trifluoro-ethyl)-piperazin-1l-yl]-pyrido[3,4-d]pyrimidin-2-yl}-pyridin-2-yl)-(2,6-difluoro-phenyl)-amine;-   (4-{5-Cyclopropyl-4-[3-(2,2,2-trifluoro-ethyl)-piperazin-1l-yl]-pyrido[3,4-d]pyrimidin-2-yl}-pyridin-2-yl)-phenyl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[(R)-1-(3-fluoro-phenyl)-ethyl]-amine;-   4-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-benzonitrile;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-trifluoromethyl-phenyl)-amine;-   (3-Chloro-2,6-difluoro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4,6-trifluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4-difluoro-phenyl)-amine;-   4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[(R)-1-(4-fluoro-phenyl)-ethyl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[(R)-1-(2,6-difluoro-phenyl)-ethyl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-5-fluoro-pyridin-2-yl]-phenyl-amine;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-4-carboxylic    acid isopropylamide;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-4-carboxylic    acid amide;-   N-(1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-yl)-acetamide;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-4-carboxylic    acid (2-fluoro-ethyl)-amide;-   N-{4-[5-Cyclopropyl-4-((S)-3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   2-(2-Chloro-pyridin-4-yl)-5-cyclopropyl-4-((R)-3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine;-   (4-{5-Cyclopropyl-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-pyrido[3,4-d]pyrimidin-2-yl}-pyridin-2-yl)-phenyl-amine;-   (4-{5-Cyclopropyl-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-pyrido[3,4-d]pyrimidin-2-yl}-pyridin-2-yl)-(4-fluoro-phenyl)-amine;-   (4-{(5-Cyclopropyl-4-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-pyrido[3,4-d]pyrimidin-2-yl}-pyridin-2-yl)-phenyl-amine;-   (4-{(5-Cyclopropyl-4-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-pyrido[3,4-d]pyrimidin-2-yl}-pyridin-2-yl)-(4-fluoro-phenyl)-amine;-   Cyclopropanecarboxylic acid    (4-{5-cyclopropyl-4-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-pyrido[3,4-d]pyrimidin-2-yl}-pyridin-2-yl)-amide;-   Cyclopropanecarboxylic acid    (4-{5-cyclopropyl-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-pyrido[3,4-d]pyrimidin-2-yl}-pyridin-2-yl)-amide;-   (5-Cyclopropyl-2-fluoro-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-4-carboxylic    acid (2-pyrrolidin-1-yl-ethyl)-amide;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-4-carboxylic    acid methylamide;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,4-difluoro-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-fluoro-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,3-difluoro-cyclohexyl)-amine;-   1-[2-(2-Cyclohexylamino-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-4-carboxylicacid    isopropylamide;-   (+/−)-(cis)-1-[5-Cyclopropyl-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol;-   (+/−)-(trans)-1-[5-Cyclopropyl-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol;-   (+/−)-2-{4-[5-Cyclopropyl-4-((trans)-3,4-dihydroxy-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-isonicotinonitrile;-   (+/−)-(trans)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4d]pyrimidin-4-yl)-piperidine-3,4-diol;-   1-[2-(2-Cyclopentylamino-pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-4-carboxylicacid    isopropylamide;-   4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5,6-trifluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,3,6-trifluoro-pyridin-4-yl)-amine;-   Biphenyl-4-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   4-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-benzoic    acid;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-4-carboxylic    acid (2-hydroxy-ethyl)-amide;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-4-carboxylic    acid dimethylamide;-   4-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-pip    erazine-1-carboxylic acid amide;-   1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-pip    eridin-4-ol;-   5-Cyclopropyl-2-(2-fluoro-pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   {4-[4-(4-Amino-piperidin-1-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   {4-[5-Cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2-fluoro-phenyl)-amine;-   {4-[5-Cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   {4-[5-Cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(4-fluoro-phenyl)-amine;-   {4-[5-Cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,6-difluoro-pyridin-2-yl)-amine;-   (+/−)-(1RS,2RS,4SR)-Bicyclo[2.2.1]hept-2-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   {4-[4-(4-Aminomethyl-piperidin-1-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   [5-Cyclopropyl-2-(2-phenylamino-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(S)-1-pyrrolidin-2-ylmethyl-amine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(S)-1-pyrrolidin-2-ylmethyl-amine;-   [4-(5-Cyclopropyl-4-[1,4]diazepan-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-fluoro-phenyl)-amine;-   Bicyclo[1.1.1]pent-1-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-3-fluoro-pyridin-2-yl]-phenyl-amine;-   [4-(5-Cyclopropyl-4-[1,4]diazepan-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-phenyl)-amine;-   (+/−)-cis-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-fluoro-cyclobutyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5-difluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5-difluoro-pyridin-4-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,2,2-trifluoro-1-phenyl-ethyl)-amine;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-3-carboxylic    acid methylamide;-   {4-[4-(3-Amino-pyrrolidin-1-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   {4-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-phenyl}-acetic    acid;-   [4-(5-Cyclopropyl-4-piperidin-1-yl-pyrido[3,4d]pyrimidin-2-yl)-pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine;-   3-{4-[5-Cyclopropyl-4-((3R,4S)-3,4-dihydroxy-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-benzonitrile;-   Chroman-4-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   N-(1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-pyrrolidin-3-yl)-acetamide;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-4-isopropyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-ethyl-2-fluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-5-isopropyl-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-ethyl-2-fluoro-phenyl)-amine;-   {4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   {4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(4-fluoro-phenyl)-amine;-   (R)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-piperidin-3-ol;-   [(R)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidin-3-yl]-methanol;-   [(S)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidin-3-yl]-methanol;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-4-carboxylic    acid ethylamide;-   (6-Cyclopropyl-2,4-difluoro-pyridin-3-yl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (6-Cyclopropyl-2-fluoro-pyridin-3-yl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-pyrrolidine-3-carboxylic    acid methylamide;-   (S)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidin-3-ol;-   1-(3-{4-[5-Cyclopropyl-4-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-phenyl)-piperidin-4-ol;-   1-{5-Cyclopropyl-2-[2-(3-piperazin-1-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ol;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[1-(1-methyl-1H-pyrazol-4-yl)-ethyl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-fluoro-6-morpholin-4-yl-pyridin-3-yl)-amine;-   1-{5-Cyclopropyl-2-[2-(1-piperidin-4-ylmethyl-1H-pyrazol-4-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ol;-   4-((R)-3-Benzyloxymethyl-piperazin-1-yl)-2-(2-chloro-pyridin-4-yl)-5-cy    clopropyl-pyrido[3,4-d]pyrimidine;-   (3-Cyclopropyl-phenyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-yl)-(4-methyl-piperazin-1-yl)-methanone;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-4-carboxylic    acid (2-dimethylamino-ethyl)-amide;-   (S)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-piperidin-3-ol;-   (R)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidin-3-ol;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-4-carboxylic    acid (2-methoxy-ethyl)-amide;-   4-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-3,5-difluoro-benzonitrile;-   (1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-yl)-piperazin-1-yl-methanone;-   4-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-benzamide;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine;-   1-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-4-carboxylic    acid (2-methylamino-ethyl)-amide;-   6-{4-[5-Cyclopropyl-4-((cis)-3,4-dihydroxy-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-ylamino}-pyridine-2-carbonitrile;-   6-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-pyridine-2-carbonitrile;-   1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-3,3-difluoro-piperidine-4,4-diol;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4,6-difluoro-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,5-difluoro-pyridin-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyridin-2-yl-amine;-   (3R,4S)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-piperidine-3,4-diol;-   (3R,4S)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-piperidine-3,4-diol;-   (3S,4S)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-piperidine-3,4-diol;-   (3S,4S)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-piperidine-3,4-diol;-   {4-[5-Cyclopropyl-4-(2-methylamino-ethoxy)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-fluoro-pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-(piperidin-4-yloxy)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-methyl-1H-pyrazol-4-ylmethyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-phenethyl-amine;-   [4-(5-Cyclopropyl-4-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine;-   [4-(4-Azetidin-1-yl-5-cyclopropyl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-fluoro-6-methoxy-pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-(3,5-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,6-difluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-5-fluoro-pyridin-2-yl]-(2,6-difluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-5-fluoro-pyridin-2-yl]-(4-fluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-piperazin-1-yl-phenyl)-amine;-   [4-(4-Azetidin-l-yl-5-cyclopropyl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-piperazin-1-yl-phenyl)-amine;-   N-{4-[4-((R)-3-Benzyloxymethyl-piperazin-1-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   {4-[5-Cyclopropyl-4-((R)-3-methanesulfonylmethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   N-{4-[5-Cyclopropyl-4-((R)-3-methanesulfonylmethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-acetamide;-   {4-[5-Cyclopropyl-4-((R)-3-methanesulfonylmethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(4-fluoro-phenyl)-amine;-   {4-[5-Cyclopropyl-4-((R)-3-methanesulfonylmethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   Cyclopropanecarboxylic acid    {4-[5-cyclopropyl-4-((R)-3-methanesulfonylmethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-amide;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,4,6-trifluoro-pyridin-2-yl)-amine;-   N-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-N′-methyl-ethane-1,2-diamine;-   N-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-N′,N′-dimethyl-ethane-1,2-diamine;-   1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-azetidin-3-ol;-   1-{5-Cyclopropyl-2-[2-(3-piperazin-1-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-azetidin-3-ol;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-isopropyl-1H-pyrazol-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-ethyl-5-methyl-1H-pyrazol-3-yl)-amine;-   [4-(5-Cyclopropyl-4-piperidin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperidin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,    4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5-difluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-fluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,    4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-fluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,4,6-trifluoro-pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-(3,5-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   (R)-4-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperazine-2-carbonitrile;-   {4-[5-Cyclopropyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-pip    eridin-4-yl-amine;-   {4-[5-Cyclopropyl-4-(piperidin-4-ylsulfanyl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   (3S,4S)-1-(5-Cyclopropyl-2-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-pyridin-4-yl}-pyrido[3,4-d]pyrimidin-4-yl)-pyrrolidine-3,4-diol;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-cyclopropyl-1H-pyrazol-4-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[1-(tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-amine;-   (1-Cyclopentyl-1H-pyrazol-4-yl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   N-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-N,N′,N′-trimethyl-ethane-1,2-diamine;-   {4-[5-Cyclobutyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,    6-difluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,    4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,6-difluoro-pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3-fluoro-pyridin-2-yl)-amine;-   (6-Chloro-3-fluoro-pyridin-2-yl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl[3,4-d]pyrmdn-2-yl)-pyridin-2-yl]-[(R)-1-(3,6-difluoro-pyridin-2-yl)-ethyl]-amine;-   N-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-N′,N′-dimethyl-butane-1,4-diamine;-   [4-(4-Azepan-1-yl-5-cyclopropyl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine;-   1-{5-Cyclopropyl-2-[2-(6-fluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ol;-   (R)-1-{5-Cyclopropyl-2-[2-(6-fluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-3-ol;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5,6-trifluoro-pyridin-2-yl)-amine;-   {4-[5-Cyclobutyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,5,6-trifluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;-   ((R)-1-Cyclopropyl-ethyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   ((R)-1-Cyclohexyl-ethyl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (5-Cyclopropyl-3-fluoro-pyridin-2-yl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   1-{4-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-piperidin-1-yl}-2,2-dimethyl-propan-1-one;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrdo[3,4-d]pyrmdn-2-yl)-pyridin-2-yl]-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-amine;-   {4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,5,6-trifluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl]-(1-methanesulfonyl-piperidin-4-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[1-(2-fluoro-phenyl)-1H-pyrazol-4-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[1-(2,6-difluoro-phenyl)-1H-pyrazol-4-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[1-(2,4,6-trifluoro-phenyl)-1H-pyrazol-4-yl]-amine;-   1-{5-Cyclopropyl-2-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ol;-   4-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-3,5-difluoro-benzamide;-   (1 S,2    S,4R)-Bicyclo[2.2.1]hept-2-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (1    R,2R,4S)-Bicyclo[2.2.1]hept-2-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-(2-dimethylamino-ethoxy)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,5,6-trifluoro-pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-(4,7-diaza-spiro[2.5]oct-7-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   {4-[5-Cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,5,6-trifluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(1-methyl-1H-pyrazol-3-yl)-amine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;-   1-{5-Cyclopropyl-2-[2-(3-morpholin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ol;-   ((R)-1-Cyclohexyl-ethyl)-{4-[5-cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4,6-difluoro-pyridin-2-yl)-amine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-pyrrolidin-3-yl-amine;-   {4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,6-difluoro-pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(5-trifluoromethyl-pyridin-2-yl)-amine;-   {4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3-fluoro-pyridin-2-yl)-amine;-   -[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-N-methyl-benzamide;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-3-yl-amine;-   {4-[5-Cyclopropyl-4-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   6-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-nicotinamide;-   {4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,4,6-trifluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(8-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine;-   4-((S)-3-Benzyl-piperazin-1-yl)-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine;-   [2-(2-Benzyl-morpholin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine;-   (S)—N¹-(5-Methoxy-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine;-   5-Methoxy-2-morpholin-4-yl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Methoxy-2-(2-phenoxymethyl-morpholin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   [(R)-4-(5-Methoxy-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazin-2-yl]-methanol;-   5-Methoxy-2-morpholin-4-yl-4-((R)-3-phenoxymethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine;-   [(S)-1-(5-Methoxy-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperidin-3-yl]-phenyl-amine;-   4-[(R)-3-(2-Fluoro-phenoxymethyl)-piperazin-1-yl]-5-methoxy-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine;-   5-Methoxy-4-((R)-3-methoxymethyl-piperazin-1-yl)-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine;-   4-[(R)-3-(4-Fluoro-phenoxymethyl)-piperazin-1-yl]-5-methoxy-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine;-   (2-Morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-(R)-pyrrolidin-3-yl-amine;-   [2-Morpholin-4-yl-8-(2H-pyrazol-3-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine;-   N⁴—((S)-2-Amino-3-phenyl-propyl)-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine-4,8-diamine;-   (S)—N¹-(2-Morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-3-phenyl-propane-1,2-diamine;-   5-Bromo-2-morpholin-4-yl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   Synthesis of    5-Cyclopropyl-2-morpholin-4-yl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   4-((S)-3-Benzyl-piperazin-1-yl)-5-cyclopropyl-2-morpholin-4-yl-pyrido[3,4-d]pyrimidine;-   [(S)-4-(5-Cyclopropyl-2-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-piperazin-2-yl]-acetonitrile;-   5-Methoxy-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   5-Methoxy-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   2-(2-Benzyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   2-[2-(2-Fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   2-(2-Ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5methoxy-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Methoxy-4-((R)-3-methoxymethyl-piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   {(R)-4-[5-Methoxy-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-yl}-methanol;-   4-Piperazin-1l-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   (R)-Pyrrolidin-3-yl-[2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-amine;-   5-Cyclopropyl-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   8-Chloro-5-cyclopropyl-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   5-Isopropyl-4-piperazin-1-yl-2-(l    H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   [5-Cyclopropyl-4-piperazin-1-yl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-((R)-3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-((S)-3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-4-((S)-3-cyclopropyl-piperazin-1-yl)-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine;-   4-((S)-3-Benzyl-piperazin-1-yl)-5-cyclopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-4-((S)-3-cyclopropyl-piperazin-1-yl)-2-(l1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   {(S)-4-[5-Cyclopropyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazin-2-yl}-acetonitrile;-   5-Cyclopropyl-4-piperazin-1-yl-2-(2-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   4-[5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperazine-1-carboxylic    acid ethyl ester;-   5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-ol;-   5-Cyclopropyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-4-morpholin-4-yl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-4-piperazin-1-yl-2-(2-triduteriomethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   2-(2-tert-Butyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-[2-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   2-(2-tert-Butyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-(5-fluoro-2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   (+/−)-(cis)-1-[5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol;-   (+/−)-(trans)-1-[5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-3,4-diol;-   5-Cyclopropyl-4-(3-trifluoromethyl-piperazin-1-yl)-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-4-piperidin-1-yl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-4-piperazin-1-yl-2-[2-(1-trifluoromethyl-cyclopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidine;-   1-[5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol;-   5-Cyclopropyl-2-[2-(1-phenyl-cyclopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   1-[5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidine-4-carbonitrile;-   {1-[5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol;-   {1-[5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-azetidin-3-yl}-methanol;-   1-{5-Cyclopropyl-2-[2-(1-phenyl-cyclopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ol;-   5-Cyclopropyl-4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-4-thiomorpholin-4-yl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   1-[2-(2-tert-Butyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol;-   4-Azetidin-1-yl-5-cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   1-[2-(2-tert-Butyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-[1,4]diazepan-5-one;-   (R)-1-[2-(2-tert-Butyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-ol;-   5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)spiro[1,3-dihydropyrrolo[2,3-b]pyridine-2,1′-cyclohexane];-   4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-9H-pyrido[2,3-b]indole;-   1-[5-Cyclopropyl-2-(9H-pyrido[2,3-b]indol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-ol;-   4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-9H-pyrido[2,3-b]indole;    or a salt form thereof.    87. A compound of formula (I) or a salt form thereof according to    embodiment 1 wherein G is

88. A compound of formula (I) or a salt form thereof according toembodiment 1 wherein G is

89. A compound of formula (I) or a salt form thereof according toembodiment 1 or 88 wherein G is

X is choosen from 3-15 membered heterocycloalkyl optionally substitutedby 1-28 R¹⁹, NR²⁴R²⁸, and —S(═O)_(n)R²⁸;R⁷, R⁸, R⁹ are each independently choosen from H, C₁₋₆alkyl optionallysubstituted by 1-13 R¹⁹, C₂₋₆alkenyl optionally substituted by 1-11 R¹⁹,C₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, and halogen.90. A compound of formula (I) or a salt form thereof according to any ofembodiments 1, 88 or 89 wherein R²⁴ at each occurance is independentlychoosen from H, and C₁₋₆alkyl optionally substituted by 1-13 R⁴⁹; andR²⁸ is selected from 3-15 membered heterocycloalkyl optionallysubstituted by 1-28 R⁴⁹, 4-21 membered heterocycloalkylalkyl optionallysubstituted by 1-40 R⁴⁹ and C₆₋₁₁aryl optionally substituted by 1-11R⁴⁹.91. A compound of formula (I) or a salt form thereof according to any ofembodiments 1 or 88-90 wherein R¹² and R¹³ are taken together to formC₃₋₁₁cycloalkyl optionally substituted by 1-21 R¹⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R¹⁹ or a 5-15 memberedheteroaryl optionally substituted by 1-15 R¹⁹92. A compound of formula (I) or a salt form thereof according to any ofembodiments 1 or 88-90 wherein R¹², R¹⁴ and R¹⁵ are each H and R¹³ is—NR²²R²³ or —NR³⁴C(═O)R³⁰93. A compound of formula (I) or a salt form thereof according toembodiment 92 wherein R²² and R²³ are each independently choosen from H,C₁₋₆alkyl optionally substituted by 1-13 R⁴⁹, C₆₋₁₁aryl optionallysubstituted by 1-11 R⁴⁹, C₇₋₁₆arylalkyl optionally substituted by 1-19R⁴⁹, C₃₋₁₁cycloalkyl optionally substituted by 1-21 R⁴⁹,C₄₋₁₇cycloalkylalkyl optionally substituted by 1-32 R⁴⁹, 3-15 memberedheterocycloalkyl optionally substituted by 1-28 R⁴⁹, 4-21 memberedheterocycloalkylalkyl optionally substituted by 1-40 R⁴⁹, 5-15 memberedheteroaryl optionally substituted by 1-15 R⁴⁹, and 6-21 memberedheteroarylalkyl optionally substituted by 1-27 R⁴⁹.94. A compound that is selected from:

-   2-(2-tert-Butyl-H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine;-   2-(2-tert-Butyl-H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine;-   4-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-N,N-dimethyl-benzamide;-   {4-[5-Cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,4,6-trifluoro-pyridin-2-yl)-amine;-   (+/−)-cis-1-{5-Cyclopropyl-2-[2-(3-morpholin-4-yl-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidine-3,4-diol;-   {4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-((R)-1-cyclopropyl-ethyl)-amine;-   {4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-((R)-1-phenyl-ethyl)-amine;-   2-(2-tert-Butyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclobutyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-{2-[1-(2-fluoro-phenyl)-cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   2-(2-tert-Butyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4,6-difluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine;-   (5-Cyclobutyl-3-fluoro-pyridin-2-yl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   {5-Cyclopropyl-2-[2-(3,5,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;-   (4-Chloro-1-ethyl-1H-pyrazol-3-yl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-amine;-   {4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-amine;-   {4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(1-isopropyl-1H-pyrazol-3-yl)-amine;-   {5-Cyclopropyl-2-[2-(3,4,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;-   {5-Cyclopropyl-2-[2-(3,5,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-pyrrolidin-3-yl-amine;-   {5-Cyclopropyl-2-[2-(3,4,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-pyrrolidin-3-yl-amine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-morpholin-4-yl-phenyl)-amine;-   5-Cyclobutyl-4-piperazin-1-yl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-pyrrolidin-3-yl-amine;-   Azetidin-3-yl-{5-cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-amine;-   4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-5,8-difluoro-9H-pyrido[2,3-b]indole;-   2-(2-tert-Butyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclobutyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidine;-   Azetidin-3-yl-{5-cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-amine;-   [4-Chloro-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-8-fluoro-9H-pyrido[2,3-b]indole;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(S)-pyrrolidin-3-yl-amine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-7,8-difluoro-9H-pyrido[2,3-b]indole;-   {4-[5-Cyclopropyl-4-((cis)-3,5-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,4,6-trifluoro-pyridin-2-yl)-amine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(2,2-dimethyl-piperidin-4-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6,8-difluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(5-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-((R)-1-phenyl-ethyl)-amine;-   (4-Chloro-1-ethyl-1H-pyrazol-3-yl)-{4-[5-cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-amine;-   Benzooxazol-2-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   Benzothiazol-2-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-methyl-1H-benzoimidazol-2-yl)-amine;-   (5-Cyclopropyl-3,6-difluoro-pyridin-2-yl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   5-Cyclopropyl-2-{2-[1-(4-fluoro-phenyl)-cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   {4-[5-Cyclopropyl-4-((S)-3-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-naphthalen-2-yl-amine;-   Biphenyl-3-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   {4-[5-Cyclopropyl-4-((R)-3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine;-   {4-[5-Cyclopropyl-4-((R)-3-trifluoromethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(1-methyl-1H-pyrazol-3-yl)-amine;-   {5-Cyclopropyl-2-[2-(3,4,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[2-fluoro-4-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amine;-   {5-Cyclopropyl-2-[2-(3,5,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-(R)-pyrrolidin-3-yl-amine;-   Azepan-4-yl-{5-cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-naphthalen-1-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-iso    [D3-4]uinolin-3-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1-methyl-1H-indazol-3-yl)-amine;-   {5-Cyclopropyl-2-[2-(3,4,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-yl-amine;-   5-Cyclopropyl-4-piperazin-1-yl-2-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-[2-(1-phenyl-cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   {5-Cyclopropyl-2-[2-(3,5,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[1-(tetrahydro-furan-2-yl)-ethyl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[(R)-1-(2-fluoro-phenyl)-ethyl]-amine;-   [5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-piperidin-4-yl-amine;-   [5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine;-   [5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-methyl-piperidin-4-yl-amine;-   8-Chloro-5-cyclopropyl-4-piperazin-1-yl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-pyrazolo[1,5-a]pyridin-2-yl-amine;-   {4-[5-Cyclopropyl-4-((cis)-3,5-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-amine;-   2-(2-Chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-(2-methoxymethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   4-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-ylamino}-piperidin-2-one;-   [5-Cyclopropyl-2-(1-methyl-2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(R)-pyrrolidin-3-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[D3-4]uinolin-2-yl-amine;-   (±)-2-((endo)-2-Bicyclo[2.2.1]hept-2-yl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-2-(2-methoxymethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   [5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-methyl-(1-methyl-piperidin-4-yl)-amine;-   5-Cyclobutyl-4-piperazin-1-yl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-(1-methyl-piperidin-4-yl)-amine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(1-methyl-piperidin-4-yl)-amine;-   1-(4-{5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-ylamino}-piperidin-1-yl)-ethanone;-   5-Cyclopropyl-2-[2-(1-methyl-1-phenyl-ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   2-(3-Chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   [5-Cyclopropyl-2-(2-trifluoromethyl-H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-methyl-(R)-pyrrolidin-3-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-iso[D3-4]uinolin-1-yl-amine;-   4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-9H-pyrido[2,3-b]indole-   4-(4-Piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-9H-pyrido[2,3-b]indole;-   8-Chloro-5-cyclopropyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   (±)-exo-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-7-oxa-bicyclo[2.2.1]hept-2-yl-amine;-   (2,6-Difluoro-phenyl)-[4-(4-piperazin-1-yl-5-vinyl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   {5-Cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;-   1-[4-({5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-amino)-piperidin-1-yl]-ethanone;-   1-[4-({5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-amino)-piperidin-1-yl]-ethanone;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(R)-indan-1-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(S)-indan-1-yl-amine;-   [4-(8-Chloro-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-phenyl)-amine;-   [4-(5-Cyclopropyl-8-fluoro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-phenyl)-amine;-   5-Cyclopropyl-8-fluoro-4-piperazin-1-yl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   (1-Cyclobutyl-piperidin-4-ylmethyl)-{5-cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-amine;-   Benzo[1,2,5]oxadiazol-4-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   5-Cyclopentyl-4-piperazin-1-yl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-(2-difluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-piperidin-4-ylmethyl-amine;-   5-Cyclopropyl-2-[2-(2-methoxy-1,1-dimethyl-ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-2-[2-(2-methoxy-1,1-dimethyl-ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   (1-Cyclobutyl-piperidin-4-yl)-{5-cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-amine;-   5-Cyclopropyl-4-piperazin-1-yl-2-[2-(tetrahydro-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-2-[2-(1-phenyl-cyclopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-2-(2-difluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(1-isopropyl-piperidin-4-yl)-methyl-amine;-   Benzo[1,2,5]oxadiazol-5-yl-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   5-Bromo-4-piperazin-1-yl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   2-(2-tert-Butyl-H-pyrrolo[2,3-b]pyridin-4-yl)-8-chloro-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   2-(2-tert-Butyl-H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-8-fluoro-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Bromo-2-(2-tert-butyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   (±)-exo-5-Cyclopropyl-2-[2-(7-oxa-bicyclo[2.2.1]hept-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   (±)-exo-5-Cyclobutyl-2-[2-(7-oxa-bicyclo[2.2.1]hept-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   {5-Cyclopropyl-2-[2-(2,6-difluoro-phenylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-methyl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-indan-5-yl-amine;-   (5-Cyclopropyl-3,6-difluoro-pyridin-2-yl)-{4-[5-cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-amine;-   N-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-2,2-difluoro-2-phenyl-acetamide;-   5-Cyclopropyl-2-[2-(1-fluoro-cyclopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   {4-[5-Cyclopropyl-4-(1-methyl-piperidin-4-ylsulfanyl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(2,6-difluoro-phenyl)-amine;-   {5-Cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-(1-methyl-piperidin-4-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-amine;-   {4-[5-Cyclopropyl-4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-phenyl-amine;-   {4-[5-Cyclopropyl-4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,    5-difluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2-trifluoromethyl-benzooxazol-5-yl)-amine;-   5-Cyclopropyl-4-(piperidin-4-ylsulfanyl)-2-(2-trifluoromethyl-1H-pyrrolo[2,    3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidine;-   (±)-endo-2-(2-Bicyclo[2.2.1]hept-2-yl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   [8-Chloro-5-cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-methyl-piperidin-4-yl-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine;-   {5-Cyclopropyl-2-[2-([D3-4]uinolin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;-   [5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-methyl-piperidin-4-ylmethyl-amine;-   (1S,2R)-1-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-indan-2-ol;-   (1S,2S)-1-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-indan-2-ol;-   (1R,2S)-1-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-indan-2-ol;-   (1R,2R)-1-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-indan-2-ol;-   5-Cyclobutyl-2-[2-(2,6-difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclopropyl-2-[2-(2,6-difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   2-(2-Cyclobutyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-2-(2-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   [4-(8-Chloro-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5-difluoro-pyridin-2-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3-methyl-3H-benzoimidazol-5-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-amine;-   {2-[2-(5-Chloro-3-fluoro-pyridin-2-ylamino)-pyridin-4-yl]-5-cyclopropyl-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;-   5-Cyclopropyl-2-(2-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-2-(2-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   [3-Chloro-1-(5-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [5-Cyclopropyl-2-(2-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(3,3-difluoro-piperidin-4-yl)-amine;-   {5-Cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(3,3-difluoro-piperidin-4-yl)-amine;-   {5-Cyclobutyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;-   trans-2-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-indan-1-ol;-   (R)-2-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-2-phenyl-ethanol;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-((R)-1-naphthalen-2-yl-ethyl)-amine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[(R)-1-(2-fluoro-phenyl)-ethyl]-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(4-trifluoromethoxy-phenyl)-amine;-   {5-Cyclobutyl-2-[2-(3,5,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;-   (S)-2-[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-ylamino]-2-phenyl-ethanol;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-((R)-1-naphthalen-1-yl-ethyl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,2-difluoro-2-phenyl-ethyl)-amine;-   {5-Cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-ylmethyl-amine;-   {5-Cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(tetrahydro-pyran-4-yl)-amine;-   {8-Chloro-5-cyclopropyl-2-[2-(3,5,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;-   {8-Chloro-5-cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;-   (5-Chloro-3-fluoro-pyridin-2-yl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   {5-Cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-(tetrahydro-pyran-4-yl)-amine;-   (4-{5-Cyclopropyl-4-[3-(tetrahydro-pyran-4-yl)-pyrrolidin-1-yl]-pyrido[3,4-d]pyrimidin-2-yl}-pyridin-2-yl)-(3,5-difluoro-pyridin-2-yl)-amine;-   {5-Cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(4-methyl-piperidin-4-yl)-amine;-   {5-Cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(3,3-dimethyl-piperidin-4-yl)-amine;-   {5-Cyclopropyl-2-[2-(3,5,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(3,3-dimethyl-piperidin-4-yl)-amine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,3-dimethyl-indan-1-yl)-amine;-   [4-(8-Chloro-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5,6-trifluoro-pyridin-2-yl)-amine;-   5-Cyclopropyl-2-[2-(3-fluoro-pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-2-[2-(3-fluoro-pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-2-[2-(1-phenyl-cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-4-piperazin-1-yl-2-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-4-piperazin-1-yl-2-[2-(l-trifluoromethyl-cyclobutyl)-1H-pyrrollobutyl)[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-4-piperazin-1-yl-2-[2-(tetrahydro-furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-4-piperazin-1-yl-2-[2-(tetrahydro-furan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidine;-   {5-Cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(3-fluoro-piperidin-4-yl)-amine;-   [4-(5,8-Dicyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5,6-trifluoro-pyridin-2-yl)-amine;-   [4-(5,8-Dicyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5-difluoro-pyridin-2-yl)-amine;-   [4-(5,8-Dicyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(2,6-difluoro-phenyl)-amine;-   2-(2-tert-Butyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5,8-dicyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   [4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(6-fluoro-pyridazin-3-yl)-amine;-   5-Cyclopropyl-4-piperazin-1-yl-2-[2-(tetrahydro-furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidine;-   (2,6-Difluoro-phenyl)-[4-(4-piperazin-1-yl-5-trifluoromethyl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   (3,5-Difluoro-pyridin-2-yl)-[4-(4-piperazin-1l-yl-5-trifluoromethyl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;-   [4-(4-Piperazin-1-yl-5-trifluoromethyl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(3,5,6-trifluoro-pyridin-2-yl)-amine;-   {5-Cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-(3,3-dimethyl-piperidin-4-yl)-methyl-amine;-   5-Cyclopropyl-2-(2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   {4-[4-(3-Amino-piperidin-1-yl)-5-cyclopropyl-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,5-difluoro-pyridin-2-yl)-amine;-   4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole;-   6-Chloro-4-(5-cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-9H-pyrido[2,3-b]indole;-   5-Cyclopropyl-2-[2-(2-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   2-[2-(2-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   5-Cyclobutyl-2-[2-(2-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   2-[2-(2-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   {4-[5-Cyclopropyl-4-(3-methylamino-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(3,5-difluoro-pyridin-2-yl)-amine;-   N-{5-Cyclopropyl-2-[2-(3,5-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-N′-methyl-benzene-1,4-diamine;-   5-Cyclopropyl-4-piperazin-1-yl-2-[2-(1-trifluoromethyl-cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyrido[3,4-d]pyrimidine;-   4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole;-   2-(3-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidine;-   [4-(5-Cyclobutyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-(tetrahydro-pyran-4-yl)-amine;-   4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-3,3-dimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one;    or a salt therof.

1. A compound selected from the group consisting of:(5-Cyclobutyl-3-fluoro-pyridin-2-yl)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;{5-Cyclopropyl-2-[2-(3,5,6-trifluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-methyl-piperidin-4-yl-amine;(4-Chloro-1-ethyl-1H-pyrazol-3-y)-[4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-amine;[4-(5-Cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-pyridin-2-yl]-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-amine;{4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-amine;and{4-[5-Cyclopropyl-4-(3,3-dimethyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-2-yl]-pyridin-2-yl}-(1-isopropyl-1H-pyrazol-3-yl)-amine;or a pharmaceutically acceptable salt thereof.